Dosage form

Start of patent duration: 1981 06 15 Longest possible duration:

© Issued on: 1982 01 11 © inventor:

9239/76 (US) 1975 12 15 CLAIM (US) 1975 12 15 CLAIM (US) 1975 12 15 CLAIM (US) 1975 12 15 CLAIM (US) 1975 12 15 CLAIM (US) 1975 12 15 CLAIM (US) 1975 12 15 CLAIMS (US) 1975 12 15 CLAIMS (US) 1975 12 15 CLAIMS (US) 1975 12 15 CLAIMED © Dependency:

© Pamphlets considered to delineate the prior art:

AT 365 449

U.S. Patent No. 3,007,848, U.S. Patent No. 3,641,237, U.S. Patent No. 2,936,263

AT-PS 105076 US-PS 383 245 8 I-PS60216 / 65

GB-PS 7140 DE-AS 2363963

GB-PS 474409 OE-OS 2133122

Nr.365449

The solid dosage unit forms known to date in the pharmaceutical industry are divided into two basic forms, namely tablets and capsules. Both the tablets and the capsules have a wide spectrum known, for example, those coated in the viscera to dissolve in the intestinal tract, those dissolving by a variety of mechanisms over a long period of time, effervescent forms, and so forth Such conventional solid oral dosage forms have numerous disadvantages.

First, a drawback of conventional, solid, oral unit dosage forms is that they contain a plurality of different active ingredient admixed substances, termed "therapeutically inactive or non-toxic, pharmaceutical additives." Such materials or materials are among the known categories such as diluents, extractants, binders, lubricants, disintegrants, stabilizers, buffers, preservatives, etc. While it is known that these substances are indispensable in the preparation of pharmaceutical mixtures, their use nevertheless poses problems the cost of the final mold 15 and the weight of the dosage unit, etc. In addition, each supplement must be tested for potential incompatibilities with the existing drugs before use. Furthermore, certain of these materials, for example, lubricants, can lead to problems with bioavailability of the active ingredient. Also, the presence of these materials must be taken into account in analytical procedures that improve the effectiveness, etc.

the finished dosage form is tested.

A second important disadvantage of the known oral unit dosage forms is that the unit dosage form must be destroyed when tested, whereby only a small percentage of the molds actually produced can be tested. It is known that the dosage forms of a batch may vary significantly as the mean deviation 25 within each batch with respect to dosage, properties, etc., is determined by analysis of a relatively small number of samples.

The batch concept itself represents a disadvantage of conventional oral solid dosage forms in terms of economics of batch design, control and testing.

The invention has for its object to provide a method for the preparation of pharmaceutical unit dosage forms, with which unit dosage forms are obtained, which do not adhere to the said disadvantages, which is particularly economical with high efficiency of the unit dosage forms obtained and allows easy quality control.

This object is achieved by a process for the preparation of solid pharmaceutical dosage unit forms for application in body orifices which release the active ingredient (s) after administration, in which one or more medicaments are applied to a therapeutically inactive, biocompatible carrier material and the carrier material is identical to one another Pieces is divided, is dissolved, which according to the invention is characterized in that applied to a band-shaped carrier material, a continuous drug layer and the band or several der40 like bands, optionally together with at least one uncoated band, is then formed into geometrically defined bodies (are), which contain essentially the active substance inside,and that these bodies are then separated into dosage units and sealed so that their surface is free of active ingredient, and optionally during the manufacturing process, a nondestructive testing or control of the process step products is performed.

In particular, this method has the following advantages: It eliminates the need to work with individual batches as previously required; it allows a continuous on-line efficacy test as well as on-line testing of dosage forms in their preparation; it essentially eliminates the need to mix conventional pharmaceuticals such additives with the drugs except for lubricants, which may be required to improve the flow behavior of powders and / or other materials that are beneficial to product properties; it allows the preparation of pharmaceutically advantageous unit dosage forms that can be engineered to contain the drug in any

Release the desired rate, and with which a release rate is greater than that of conventional tablets and capsules. Overall, the dosage forms of the present invention provide that a greater percentage of a more accurately measured amount of medically effective substance is available at a more accurately controlled time after ingestion than is the case with conventional commercially available units.

The device for carrying out the method according to the invention is characterized in that it

a) a first device for producing a carrier material from therapeutically ineffective, biocompatible material,

b) a second device for receiving the carrier material and for continuously coating the carrier material with at least one active substance,

c) a third device for receiving the coated carrier material and for producing a solid geometric body of predetermined dimensions from the coated carrier material, in which the active substance is arranged substantially inside,

d) a fourth device which receives the geometrical body and separates it into a plurality of dosage units,

e) a fifth device, which takes up the dosage units, closes them while placing the drug completely inside, and

f) contains a device for a nondestructive on-line testing of at least one product according to the devices 1 to 5.

From the prior art, the following publications are worth mentioning, dealing with solid, distinguishable from conventional tablets dosage forms. U.S. Patent No. 3,444,858 describes a mouth-shaped form of medication comprising a strip of gelatinous material containing the medicament. The strip is divided into individual sections, each of which is connected to the next by easily tearable tapes or links. In use, a section is separated from the strip and pushed into the mouth.

A second noteworthy publication is an article in the New England Journal od Midicine, Vol. 289, no. 10 p. 533 to 535 [1973].

This article describes a process that has made women in the PRC widely available a birth control medicine. In this method, a colored sheet of water-soluble carboxymethylcellulose paper is treated with a solution of substances with progesterones and estrogens. 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 may become contaminated and / or inactivated.

Further reference is made to US Pat. No. 3,625,214, which describes a dosage form used for controlled, ie, sustained, release of medicaments. 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 layers and diffusion from the sides where exposed drug is present. In US Pat. No. 3,625,214 there is no information as to whether the dosage forms are suitable for the production in large numbers. Furthermore, there is no information about

According to US Pat. No. 3,007,848, a drug is added intermittently between two convergent edible films, which are subsequently sealed and subsequently separated into individual dosage forms. In principle, the statement of this patent does not go beyond

No. 4,654,449 which has been practiced for many years with respect to the filling of soft gelatin capsules.

However, it can not be inferred from this reference that - as in the invention - a

Volume is continuously loaded with a drug.

In the AT-PS No. 105076 the production of an elastic tablet is described, wherein the active ingredient, which usually has a bad smell, is embedded in a gelatin foil.

According to British Pat. No. 747,409, recesses are formed in a plastic film by means of vacuum, into which the medicament is added, whereupon a second plastic film thus preformed is placed over it and the two films are welded on the edge.

The ÜS-PS No. 3.641.237 relates to a drug preparation with delayed and constant release of active ingredient. The composition may be in the form of a laminate, which, however, is completely different from the laminate embodiment according to the invention.

DE-OS 2133122 relates to a sophisticated multi-layer tablet, in which classic fillers and binders are used, and which is pressed in a conventional manner 2u tablets.

In marked contrast to the teachings of said publications, the novel solid dosage forms which can be prepared according to the invention are completely isolated, are suitable for non-destructive, on-line analytical testing in large quantities during pharmaceutical production, are substantially free of pharmaceutical adjunct materials can have an adverse effect on their properties, contain no exposed drug and have excellent consistency in drug release, which increases their effectiveness.

Compared with conventional oral dosage forms such as tablets and capsules, the unit dosage forms according to the invention have several advantages: first, the dosage forms prepared according to the invention are substantially free of pharmaceutical additives, which leads to cost savings in raw materials and in the production and eliminates possible incompatibilities caused by such additives caused. Here, the difference must be made between the tapes used in the invention which can be considered as additives, and materials such as fillers, binders and the like which are blended in the medicament in conventional solid dosage forms.

Secondly, since, according to the present invention, the solid unit dosage forms are continuously prepared and analytically tested on-line nondestructively, the need for batch production as currently known eliminates appreciable cost and significantly improves quality control of finished dosage units. Characterized in that in the preparation of the dosage forms according to the invention, a device is provided, with the information from a testing station can be directly transferred back to the previous manufacturing operations, on-line corrections and adjustments are possible. Such a device facilitates the removal of only a few dosage units from any plurality which serves as a production quantity or guideline. The selection and removal of such small amounts of dosage forms offers both a major economic advantage over conventional pharmaceutical manufacturing processes and better quality control, particularly with respect to the level of active ingredient in the final dosage forms. Normally, the dosage forms are prepared by time-rate methods, ie a "quantity" of dosage forms forms a number of times between two times. This concept is unique in the pharmaceutical industry. It should be noted, however, that in any pharmaceutical preparation, a degree of non-destructive testing is necessary to test the properties of the finished product. However, such a test is required in the process according to the invention to a much lesser extent than in conventional manufacturing processes. More important, however, is the fact that such non-destructive operations, ie property evaluations, are carried out on-line with information feedback, leading to the advantages outlined above with respect to non-destructive methods.

Third, the dosage units prepared according to the invention are clearly distinguishable from conventional tablets and capsules in their appearance, shape, texture, etc., which makes them easily identifiable. The on-line, destructive 5 No.365449 free testing operations and continuous. Manufacturing operations in accordance with the invention enable on-line packaging of the unit dosage forms into individual containers, such as clear plastic strips or blister packs, thereby reducing handling costs and costs

Equipment can be saved.

Fourth, with the finished dosage forms made in accordance with the present invention, tight specifications regarding size, shape, release of drug, etc. can be easily met because the preparation of the dosage forms is very accurate, ie the drug applied evenly to the tape, the finished units accurately be formed and the band has exactly the desired properties. The dosage forms prepared according to the invention have excellent stability. They may also contain such drugs which are adversely affected by moisture because, in certain embodiments of the invention, the drug is applied to the band by electrostatic precipitation, whereby moisture that could cause the expiration of an adverse reaction, almost completely avoided. Also, when the dosage forms are made from a layered layer of tape layers, such medications can be applied to alternating tape layers known to chemists as being chemically incompatible. Thus, such a combination can be effectively stabilized without the need to resort to economically disadvantageous measures, such as the coating of one or more of such incompatible substances with an insulating material, the admixture of stabilizing adjunct materials to such drugs, the incorporation of such medicaments into separate tablet layers, which are then compressed u.ähnl. The process according to the invention can be used by one or both of the measures mentioned for foaming formulations,

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

Although the dosage forms prepared according to the invention are intended primarily for oral administration, they are also suitable for rectal and / or vaginal use. For the preparation of dosage forms of desired shape and form, the dimensions of the band as well as the manufacturing processes may be modified as appropriate. A desired release of the drug may be achieved by some variation in the composition of the band or band material. Experiments have shown that rectal and vaginal application of the solid dosage forms prepared according to the invention does not result in local irritation.

The new dosage forms can be formulated to achieve any desired release behavior, including sustained release. Regardless of the particular release properties, the dosage units produced according to the invention are characterized by a remarkable uniformity of the release of a large number of dosage units, for example 10,000 or more. A variation in the rate of release may be achieved according to the invention by varying a number of factors, such as the thickness of the tape, the composition of the tape, the presence of a wrap or outer seal on the finished tape or its composition, how tight the tape is made, and the like .ähnl. For example, a tape composition containing much sodium carboxymethylcellulose normally dissolves slowly in gastric fluids. Dosage forms made from such bands by fan-shaped folding, as described below, will open or unfold upon contact with gastric fluid, rapidly releasing the drug applied to their inner surfaces, e.g. faster than conventional tablets and capsules. However, when such a fan-folded dosage form is occluded at the folded edges with a substance such as ethyl cellulose, cellulose acetate, phthalate or zein which prevents its opening in gastric fluids, the medicament is removed by gradual release which are made of such bands by fan-shaped folding, as described below, open or unfold when in contact with gastric fluid, whereby the drug applied to their inner surfaces drug is released quickly, u.zw. faster than conventional tablets and capsules. However, when such a fan-folded dosage form is occluded at the folded edges with a substance such as ethyl cellulose, cellulose acetate, phthalate or zein which prevents its opening in gastric fluids, the medicament is removed by gradual release which are made of such bands by fan-shaped folding, as described below, open or unfold when in contact with gastric fluid, whereby the drug applied to their inner surfaces drug is released quickly, u.zw. faster than conventional tablets and capsules. However, when such a fan-folded dosage form is occluded at the folded edges with a substance such as ethyl cellulose, cellulose acetate, phthalate or zein which prevents its opening in gastric fluids, the medicament is removed by gradual release faster than conventional tablets and capsules. However, when such a fan-folded dosage form is occluded at the folded edges with a substance such as ethyl cellulose, cellulose acetate, phthalate or zein which prevents its opening in gastric fluids, the medicament is removed by gradual release faster than conventional tablets and capsules. However, when such a fan-folded dosage form is occluded at the folded edges with a substance such as ethyl cellulose, cellulose acetate, phthalate or zein which prevents its opening in gastric fluids, the medicament is removed by gradual release

No.365449 construction of the tape accessible, which leads to a constant sustained release. Because the dosage forms of the present invention allow drug release with greater speed over conventional solid dosage forms such as tablets and capsules, embodiments having such rapid release are preferred.

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

2 is a device for carrying out the method according to FIG. 1, FIG. 3 shows a device for carrying out the tight winding during the production of the dosage form, Figs. 4A, 4B and 4B show the rotary forming and layering technique of the preparation of the dosage form, Figs. 6A to 6D show the finishing and closure in the manufacture of the dosage forms by fan-shaped folding, and Figs. 7 and 8 are curves showing the release of the active ingredient in dosage forms prepared according to the invention in comparison with a conventional solid dosage form, here a capsule.

The bands used to deposit the medicament in accordance with the invention must meet numerous physical and chemical 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 preferably must self-degrade or be decomposable in body fluids and / or enzymes. However, the band may be made of non-degradable material that is easily excreted by the body. Preferably, the band is hydrophilic and readily soluble in water. These properties must not be adversely affected by the py value of the gastric fluid, but should thereby be advantageously favored. The tape must be completely neutral to the drug applied to it and should not release any substance that would cause in situ incompatibility with the drugs when in contact with gastric fluid.

The tape must be stable for extended periods of time at elevated temperatures and humid environments 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 thereon by electrostatic precipitation.

The tape must be perfectly workable 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 thickness), it must have good tensile and tear strength and it must have an acceptable fold durability, if it has to withstand certain manufacturing processes, as explained below.

The belt surface must permit the on-line analytical procedures described below, must be coatable with and hold powdered medicament that is electrostatically or otherwise applied thereto, and be suitable for printing.

The tape must be closable by known sealing methods in a simple manner. However, sealing must be feasible even with moisture and heat that does not adversely affect the drug contained in the dosage form. In addition, the tape must have a sufficient flame resistance, so that such Verschließvorgänge are possible.

In certain cases, the tape must have a "memory", ie it must have sufficient resilience to rapidly reverse the manufacturing process upon contact with gastric fluids and "open", thereby releasing the drug for absorption. By "opening" is meant, for example, that the dosage form, when made by fan-shaped folding, opens like a bladder, and when made by tightly wrapping, unwinds, and so on.

Finally, the tape must have other properties, for example, have acceptable taste and odor, properties that will be apparent to those skilled in the art from the following description.

- 7 No. 365449

As stated above, the tapes used in the invention are preferably water-soluble or water-dispersible. There are two basic mechanisms by which the ligaments used in the invention are constructed so as 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 on contact with water, causing the tape to break or break. Second, the tape material may contain water-soluble and insoluble components. When in contact with water, the soluble constituents of such a material tend to dissolve, while the insoluble constituents tend to precipitate, causing the band to break. The latter mechanism of the band break is not as fast as the former. Examples of suitable water-soluble ingredients are methylcellulose

u.ähnl. Examples of non-water-soluble ingredients are ethyl cellulose and the like.

The tape formulations used to make the new dosage forms are basically two 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 constituents with certain formulations, such as disintegrants, diluents 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 constituents with certain formulations, such as one or more organic film 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 natural and chemically modified starch and dextrins, proteins such as gelatin, cellulose derivatives such as sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose and the like. other polysaccharides such as pectin, acacia, xanthan gum, guar gum, algin and the like, plastics such as polyvinylpyrrolidone, polyvinyl alcohol and the like. Preferred film formers are hydroxypropyl cellulose and sodium carboxymethyl cellulose. While not critical, the concentration of the film-forming component in the polymeric tape is preferably between about 5 to about 95 weight percent, most preferably between about 40 and about 90 weight percent.

The film-forming substances mentioned are also examples of the film-forming substances of

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 ingredient in the paper tape formulations is also not critical. However, if such a component serves as a binder or explosive or solvent for the fibrous material, it should be about

Not exceeding 40% by weight, preferably between about 2 and 20% by weight, and most preferably between about 4 and 10% by weight.

The fibrous component of the paper tape formulations may be any commercially available natural or artificial fiber which has been found to be non-toxic in tests. Examples of such fibers are cotton, linen, cellulose, synthetically modified cellulose, rayon (registered trade mark), textured vegetable protein, collagen and the like.

In order to obtain the required machinability and mechanical properties, the polymeric tapes used in the practice of the invention contain an effective amount of a softening ingredient. Such plasticizers are, for example, glycerol, fatty acid residues of the ether of sorbitan with 20 moles of ethylene glycol, for example oleate, stearate, certain mixtures of mono- and 50-di-glycerides of saturated fatty acids u.ähnl. Preferably, such plasticizers are present in an amount between about 1 and 60% by weight, preferably between about 10 and 50% by weight of the ribbon material.

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

Furthermore, the formulations of both tape types may contain one or more fillers or extenders as are well known. Such ingredients include, for example, opacifying fillers such as titanium dioxide, lime, kaolin, and the like, microcrystalline cellulose, calcium carbonate, and the like. Some of the ingredients listed may have more than one function and therefore fall into more than one of the categories listed above. For example, calcium carbonate can act both as a clouding agent and as a dispersing agent, certain starches can act as a binder and as a disintegrant, and so on.

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 dioctyl sodium sulfosuccinate and the like. The bands may also contain ingredients such as pharmaceutically acceptable colorants, preservatives, and the like. contain.

Finally, both types of tape formulations usually contain a volatile solvent, for example water, certain organic solvents, for example ethyl alcohol or combinations of such solvents, for example a mixture of alcohol and water, which is removed during the production of the tape.

Specific examples of ribbon compositions or materials useful in this invention are shown below.

<td colspan="3">Polymeric films or ribbons that break down in an aqueous environment due to swelling agents are as follows:</td>

<td></td><td>component</td><td>Wt .-%</td>

<td>I</td><td>hydroxypropyl methylcellulose</td><td>45.69</td>

<td></td><td>Acacia Gelatin, extra fine,</td><td>19.44</td>

<td></td><td>solubilized dioctyl sodium</td><td>32.08</td>

<td></td><td>75% aqueous solution</td><td>0.09</td>

<td></td><td>titanium dioxide</td><td>1.94</td>

<td></td><td>lecithin</td><td>0.75 100</td>

<td>II</td><td>Purified starch</td><td>33.06</td>

<td></td><td>carboxymethylcellulose</td><td>33.06</td>

<td></td><td>propylene glycol</td><td>33.06</td>

<td></td><td>sodium benzoate</td><td>0.55</td>

<td></td><td>sorbic acid</td><td>0.28 100.01</td>

<td>III</td><td>hydroxypropyl methylcellulose</td><td>55.19</td>

<td></td><td>cellulose acetate phthalate</td><td>2.99</td>

<td></td><td>cornstarch</td><td>28.66</td>

<td></td><td>propylene glycol</td><td>9.87</td>

<td></td><td>titanium dioxide</td><td>1.52</td>

<td></td><td>dioctyl sodium</td><td>1.52</td>

<td></td><td>lecithin</td><td>0.25</td>

100

- 9 No. 365449

component

IV Hydroxypropylmethylcellulose Cellulose acetate phthalate Calcium carbonate Propylene glycol Titanium dioxide

dioctyl sodium

lecithin

Wt .-%

64,00

3.10

21.74

9.06

0.91

0.91

0.30

100.02

The formulations I to IV are sealed or closed by heat and pressure. Formulation IV destroys itself due to the presence of insoluble polymeric agents in an aqueous environment.

Preferred paper formulations useful in this invention contain between about 70 to 99 weight percent, preferably between about 90 and 96 weight percent fiber, for example hardwood or softwood fibers or blends thereof, between about 1 and about 30 weight percent, preferably between about 4 and 10% by weight of a disintegrant selected from the group of sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, 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 said substances to act as disintegrating agents in paper formulations is unexpected because of the fact that that they have been used in papermaking in other quantities and fulfill another function. For example, sodium carboxymethyl cellulose has hitherto been used in papermaking in small quantities, ie, 0.1% by weight or less, as an aid in dispersing the fibers in paper formation. In contrast, it has been found that when sodium carboxymethylcellulose or the other substances listed above are added in large amount, ie up to 30% by weight, after the paper tape has been formed but while it is still wet, it acts as a disintegrating agent the time of addition of these substances is critical for their function as disintegrant. The disintegrants are preferably added as a solution to the solvent used to make the paper web. It turned out that the above-mentioned disintegrants, when added to the belt as described, cover the fibers. When the finished dosage form comes in contact with water, the disintegrant swells, forcing the fibers to rupture the tape. The wetting agents, when present, act to assist the ingress of water to the disintegrant and thereby promote tearing of the web.

The tapes used in the invention are made in a conventional manner, for example as is common in the papermaking and film making industries. For example, the polymeric ribbons may be applied to a suitable substrate such as Mylar, stainless steel , release paper and the like. to be poured. 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 known. However, most of the relevant films here are dried at temperatures between about 25 and 105 ° C, 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-forming component is a modified food starch, hydroxypropyl cellulose or other extrudable polymer. The mechanical details of the extrusion process, such as the apparatus used, the extrusion force, the shape and the temperature of the orifice, are considered to be known to those skilled in the art and can be altered in a known manner to obtain the physical properties of the ribbons described below.

The paper tapes which can be used according to the invention are produced using conventional papermaking machines, for example on Fourdrinier paper machines. In all cases, however, the strip must be uniform both in its thickness and in its width. The bands are between about 0.03 to about 0.3 mm, preferably between about 0.038 to about 0.123 mm thick. A normal width of these bands is 30 cm, although the width of the band is not particularly critical in the practice of the invention. The band can be made in any length. Because the dosage forms prepared according to the invention are very well suited for high speed production, however, the tapes should be made in large quantities,

Referring to Fig. 1, a block -10- illustrates the tape making from the above formulations. At the time of manufacture or shortly thereafter, the tape is tested (block -11- in Fig. 1) with various tests carried out wholly or partly automatically To ensure the integrity of the tape, as will be explained in more detail below. The tests of the tape may take place in the formation of the tape or at a suitable later location by means which cooperate with the tape-making apparatus or by other apparatus, and may be performed at any other location.

The active ingredient to be applied to the tape is prepared and stored in containers for use as indicated generally at -22 in Fig. 2, with Fig. 2 very diagrammatically showing the various apparatuses for carrying out the steps illustrated in Fig. 1. The prepared active ingredient is fed to an assembly generally designated by -23- in Figure 2, where the size reduction of the particles of the active ingredient and their testing takes place, as indicated at -12- in Fig.l. This step will be described in more detail below; with the step -13- and the device -23- is to be brought about a uniform flow, so bring an accurate and uniform on (block -14- Fig.l) of the active ingredient on the tape is possible, which in Fig.2 with -24- is designated. It should be noted that the system illustrated by way of example in Fig. 2 relates to the application of dry, particulate material to the belt in the dry state. The invention also includes wet deposition of the active ingredient on the belt. FIG. 2 shows that part of the invention in which the tape is prepared and stored for later use, ie in which the tape test (stage 11 in FIG. 1) is carried out, for example when the tape is withdrawn from the storage roll -20-. This test can be done before winding and storing the tape or can be done additionally, as indicated in Figure 2 with -21-. The details of the tape inspection will be described in more detail below. Figure 2 shows an example of the application of dry, particulate material to the belt in the dry state. The invention also includes wet deposition of the active ingredient on the belt. FIG. 2 shows that part of the invention in which the tape is prepared and stored for later use, ie in which the tape test (stage 11 in FIG. 1) is carried out, for example when the tape is withdrawn from the storage roll -20-. This test can be done before winding and storing the tape or can be done additionally, as indicated in Figure 2 with -21-. The details of the tape inspection will be described in more detail below. Figure 2 shows an example of the application of dry, particulate material to the belt in the dry state. The invention also includes wet deposition of the active ingredient on the belt. FIG. 2 shows that part of the invention in which the tape is prepared and stored for later use, ie in which the tape test (stage 11 in FIG. 1) is carried out, for example when the tape is withdrawn from the storage roll -20-. This test can be done before winding and storing the tape or can be done additionally, as indicated in Figure 2 with -21-. The details of the tape inspection will be described in more detail below. The invention also includes wet deposition of the active ingredient on the belt. FIG. 2 shows that part of the invention in which the tape is prepared and stored for later use, ie in which the tape test (stage 11 in FIG. 1) is carried out, for example when the tape is withdrawn from the storage roll -20-. This test can be done before winding and storing the tape or can be done additionally, as indicated in Figure 2 with -21-. The details of the tape inspection will be described in more detail below. The invention also includes wet deposition of the active ingredient on the belt. FIG. 2 shows that part of the invention in which the tape is prepared and stored for later use, ie in which the tape test (stage 11 in FIG. 1) is carried out, for example when the tape is withdrawn from the storage roll -20-. This test can be done before winding and storing the tape or can be done additionally, as indicated in Figure 2 with -21-. The details of the tape inspection will be described in more detail below. when the tape is withdrawn from the storage roll -20-. This test can be done before winding and storing the tape or can be done additionally, as indicated in Figure 2 with -21-. The details of the tape inspection will be described in more detail below. when the tape is withdrawn from the storage roll -20-. This test can be done before winding and storing the tape or can be done additionally, as indicated in Figure 2 with -21-. The details of the tape inspection will be described in more detail below.

The test of the uncoated band in the test device -21- can be done in various ways. Holes, patches, 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 transimission and reflection. The continuous helium-neon laser beam is passed over the belt by means of a mirror mounted on a galvanometer. The position of the mirror is controlled electronically so that the 40 position of any defect can be detected on the tape. The reflected or transmitted light is detected by means of a linear photodiode disposed behind an interference filter to turn off space (stray) light. The electrical output signal is used to count the number of defects and to determine their size and distribution along the ribbon. This is done by analyzing the output of the detector with a pulse height pulp analyzer.

Another method of testing the tape at significantly faster tape speeds uses a parallel array of photodiodes arranged across the tape. Each pbotodiode has its own threshold detector system and digital logic that allows characterization of the low resolution defect size and location of the defect 50. The output signal can be processed to give any size distribution and location of the defects on the tape.

The physical thickness of the tape is measured by means of a parallel array of tape rollers arranged in precision bearings. These rollers touch the tape and are on

Transducer connected electronically the location with an accuracy of at least 0.002 mm

Record No. 365449. A similar device for measuring thickness may consist of pneumatic sensors floating over the belt on an air film. This system has the advantage that it does not touch the tape.

The mass thickness (weight per unit area) or the basis weight of the bands is determined using a non-contact beta-beam or x-ray technique. These systems measure the absorption of beta rays or X-rays that radiate through the tape. This absorption is related to mass thickness. In another system, the electrical resistance between two tape contacting electrodes is measured to determine the basis weight of

To determine bands with known moisture content.

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

The belt passed through the tester -21- is guided by a pulley arrangement shown in Fig. 2 so as to move very close to an active component applying device -24- in which the belt is loaded with active ingredient. The apparatus is followed by means 25 for on-line analysis / testing, for example, the uniformity of the active ingredient content of the coated tape, where the tape is preferably in the form of a single layer there before the active ingredient 25 Part is arranged in its interior.

A preferred method of non-destructive on-line analysis of the active tape-coated component is X-ray absorption. In this method, low energy X-rays having a frequency peak corresponding to the absorption edge of the atoms deposited on the tape are directed through the coated tape. The absorption of X-rays 30 is related to the absorption of active ingredient plus band. When the active ingredient is applied to the tape by wet coating, this method of analysis can be used both before and after drying.

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

For non-destructive on-line analysis of the deposited active ingredient may also be in

Reflection or transmission working spectrophotometry can be used. Reflective spectrophotometry is used in the near ultraviolet to determine the active ingredient loading. This technique can be used with any solid active ingredient that has optical absorption in a suitable wavelength range.

Transmission spectrophotometry may also be used for nondestructive, on-line analysis of active tape-applied component. With respect to the wavelength ranges in which the active ingredient selectively absorbs, a light source, a monochromatizing element and a detector are selected. The wavelength range must be in a spectral range in which the band itself is not strongly absorbed. Such regions are in the near infrared and infrared regions of the spectrum associated with functional groups in the bands used in the invention. To cover a small wavelength range of interest, a fast wavelength scanning system is used. The output of the detector is averaged over several samples,

The signal data is then further processed to provide an increase in sensitivity

- 12 Nr.365449 to obtain the first derivative of the transmission with respect to the wavelength. This is similarly done for other wavelength ranges that respond to other components in the system. In this way, the water content, the basis weight of the tape and the content of active

Be determined at the same time.

Another method of analyzing the active ingredient loading is molecular fluorescence. By means of a suitable filter combination, excitation radiation is generated in the ultraviolet or visible region of the spectrum. The fluorescence of the active ingredient is measured with a broadband filter-detector combination selected according to the fluorescence peak; To eliminate the excitation energy, a blocking filter is used. The detector used in this method is preferably a photon counter that counts individual photo events and allows high sensitivity and linearity in low light conditions. In this analysis, precautions must be taken to limit the photodecomposition of the active ingredient by the excitation radiation.

The coated tape may be stored temporarily or is preferably fed directly to manufacturing equipment (stage 16-16 in Fig. 1) and singulator (stage -17- in Fig. 1) to make dosage forms. These devices are shown in Figure 2 as a series of knives 26-2 for cutting the coated strip into a plurality of endless strips followed by a layer-type processing and separating device 27, ie, the endless strips are stacked on top of each other an endless stack is produced, which is pressed and finally singulated according to the invention, as will be described below.

The singulated dosage forms are then finished and packaged in a device (step -18- in Fig. 1), which is shown schematically at -28 and 29- in Fig. 2, to be subsequently distributed. In connection with this work step, a check is carried out (for example -30- in Figure 2). The purpose of the final testing of the individual dosage units is to determine the size, shape, integrity, identity, presence and accuracy of an imprint, and active ingredient content. Except for the active ingredient content test, this entire test is non-destructive. For the analysis of the content of the active ingredient and the characteristic properties, a statistical sample of dosage units is taken from the production line and analyzed for destruction in terms of effectiveness and properties, ie dissolution properties. This is done by solution spectrophotometry, as described below.

An optical scanning system may be used to inspect all production units for size, shape, integrity, identity, and the presence and accuracy of an imprint. This system includes a light source 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 is to compare the sample image with a standard image using an image mask technique.

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

Prior to the finishing stage, an on-line analysis for dissolution uniformity and content is performed in step -19- (Fig. This analysis is done by means of a non-individualized device that may include and / or be controlled by a computer or similar central processing or logic device. A random sampling mechanism removes one dosing unit from the end of the production line at a rate of 25 to 120 units / min, preferably 40 to 60 units / min. Each unit is sequentially fed to a conventional automatic weighing apparatus in which it is weighed by means of a nondestructive device, the associated information being stored. Statistically selected units are then sequentially arranged in a conventional automatic analysis system. The dosing unit is agitated in a solvent for the active ingredient at a suitable rate. The amount of active ingredient dissolved at time tj less that at time t. dissolved amount, divided by t. - t. , is called

Dissolution speed taken. The appropriate time interval (tj-U) is preselected and changes for individual drugs. A suitable time interval 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 the active ingredient, after which the solvent is analyzed for the content of active ingredient. The amount of active ingredient of this analysis plus the amounts from the samples at time L and provides the total amount present in the dosage form. This information is also recorded and saved. 10 If the weight, thickness, dissolution rate and analysis of the drug are within predetermined limits, the units are acceptable.

Referring to Fig.l be further noted that according to the invention additionally the functions or properties described below are monitored. The tape inspection is done, for example, continuously tape color, thickness, context, smudges and defects of any kind. These functions can be done by electronic and / or optical instruments or by visual observation.

To check the tape is the arrangement of a "flag" on the tape, where ever

Error or defect is detected. In addition, an apparatus may be provided which, whenever a defect is detected on the tape, automatically or under operational control produces an expression indicating that there is a defect of some sort on the tape at a certain distance in the direction of movement, the term contains an identification of the nature of the defect, for example as a hole, a black spot or other error, etc.

The device for producing the printout may be the same device that performs the "flagging" of the tape itself. Such a device is commonly used in the manufacture of fabric or fabric and the test of the fabric, for example, except that the handling and testing of the tape in the present case would be carried out according to careful manufacturing requirements.

Additionally, the same or additional conventional testing equipment would measure the tape thickness. This could be done with a visual display required by an operator, or could be done in a measuring device connected to a logical array with upper and lower limits for the strip thickness, and once the thickness of the strip is out of bounds, it will also be a printout and a flag would be placed on the tape as described above. An embodiment of a device for measuring the thickness of the belt could be a measuring device operating with X-rays or beta-rays or a device similar to that for measuring the mass thickness of the belt.

In the operation -13- of Fig.l, which relates to the reduction of the particle size and the flow control, the following function monitoring should happen. The unloaded^w Although the tape itself has already been tested in terms of its thickness and errors, according to the invention a similar test after loading the tape with active ingredient (s) is provided. For example, an X-ray measuring device would again be useful for measuring the thickness of the loaded strip, which would allow conclusions to be drawn as to the amount of active 45 constituent applied to the strip compared to the previously measured thickness of the unloaded strip. In addition, within the scope of the invention means for monitoring the actual amount are provided in order to determine the amount of active ingredient loaded on the belt. The test of the loaded tape could be done by passing the loaded tape back through the same device which performs the tape inspection of step -11- in FIG.

⁵⁰ The means for applying the active ingredient (reference numeral -14- in Fig.l) is controlled by a feedback from the on-line analysis of the content of active ingredient on the tape. For example, electrical signals from the on-line analyzer (digital or analog) representing the active ingredient loading (weight of active ingredient area

- 14 No. 365449 of the coated tape), in a feedback mode (reference numeral -15- of Fig.l) used to control the amount of deposited on the tape during the deposition of the active ingredient. These feedback signals are supplied, for example, to a minicomputer which generates a suitable correction signal for the deposition process. This correction signal causes either an increase or a decrease in the loading of active ingredient, so that the load remains within a narrow range around the target value. For example, in the dry deposition of the powder with the active ingredient is introduced into the deposition device. The correction signal is used here to control the feed rate and corresponding to the active ingredient loading.

For wet deposition, for example, the correction signal may be used to vary the amount of coating formulation applied to the tape. For example, the gap between metering rollers or between a metering blade and an application roller is changed to change the active ingredient loading. In reverse roll coating, the rotational speed of the application roller is changed to change the active ingredient loading. Another means for controlling the 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 to provide the correct concentration;

The methods of "incorporating" the active ingredient into the new dosage forms is a radical departure from methods whereby active ingredients are incorporated into conventional solid dosage forms such as tablets, capsules, dragees, suppositories, etc. Although the methods and devices used in the invention may vary slightly; However, the fundamental principal aim is the uniformity of the deposition, that is to apply the active ingredient on the moving belt surfaces in an extremely uniform manner or deposit it. The mode of application of the active ingredient of the present invention is unique and associated with many advantages over methods of preparation conventionally used in the pharmaceutical industry.

Because the active ingredient is deposited on the surface of an edible tape, which is then processed to contain the active ingredient completely inside, there is no need to add to the active ingredient ordinary pharmaceutical extractants, fillers, preservatives and the like. which saves costs and, more importantly, eliminates a source of potential incompatibilities and quality control issues. On the tape according to the invention a uniform coating with active ingredient is applied. The tape is then subdivided into individual dosage forms by straight or geometric division, whereby a uniformity of the active ingredient strength is achieved in a large number of dosage forms, which is substantially above that with single batch production as currently accepted in the pharmaceutical industry. In marked contrast to the invention, conventional pharmaceutical manufacturing operations require that the active ingredients and therapeutically neutral pharmaceutical adjunct materials be prepared in bulk and then subdivided volumetrically into tablets for filling into capsules or 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 desired dosage from the presently used level between 5 to 10 wt .-% to about 1 to 5 wt .-%, resulting in a noticeable Cost savings, especially if very expensive active substances, For example, certain hormones and antibiotics are processed. Finally, the method of the present invention, to deposit or unload the active ingredient on the belt, allows a continuous non-destructive on-line physical parameter metering which favors maintaining a high uniformity of the amount of active ingredient in a variety of dosage forms.

The active ingredient may be applied to the tape in wet or dry form, with the dry form being preferred. In any case, the active ingredient in one of

Nr.365449

Approachable form 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 of 1 to 100 μ. Submicron particles have heretofore been considered too fine for the preparation of pharmaceutical tablets unless previously subjected to specific techniques such as granulation, which appreciably increases the particle size and adds extractant 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 tape as a very uniform coating,

The preferred method by which the active ingredient, when in dry form, is applied to the tape is by electrostatic precipitation of a powder cloud, using techniques known in certain non-pharmaceutical arts. This method requires passage of the tape through an electrostatic field prevailing in a chamber. Fine particulate matter is introduced into the chamber, for example by means of a sustained air flow, and is deposited on the belt as it moves over an oppositely charged roller. Although this description is a great simplification, the apparatus required to achieve this result is in certain non-pharmaceutical fields of work, as well known in the manufacture of adhesives and adhesive papers. In order for satisfactory deposition to occur, the tape must have a resistance that allows the deposition of dielectric particles on the tape. Additives that may be present in the ribbon composition to achieve the proper electrical properties have been discussed above. In many cases it has been found that prior to the electrostatic deposition of the powdered active ingredient it is necessary to coat the tape with a substance which promotes adhesion of the powder to it. Examples of such substances are carboxymethylcellulose, methylcellulose 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 on the tape, which provides for adhesion of the active substance, then follows immediately on-line coating or "loading" of the band with the active substance. The adhesive then goes into action and binds the active substance particles to the belt. This is achieved by applying the tape, with heat, pressure, moisture or a suitable combination of the measures mentioned. In addition to the method of electrostatic precipitation of a powder cloud, active ingredient in the form of a fine powder may be applied to the belt in the dry state by electro-gas dynamic powder coating. In this process, the particles of active ingredient are electrically charged by being subjected to corona discharge and propelled by a gas flow into an electrically isolated chamber. The tape passes through this chamber on a metallic surface which is grounded or charged with opposite polarity to charge the charged cloud of particles of active substance. The electric field between the particles and the metallic surface pulls the particles onto the belt and deposits them there. which is grounded or charged with polarity charged to charge the charged cloud of particles of active substance. The electric field between the particles and the metallic surface pulls the particles onto the belt and deposits them there. which is grounded or charged with polarity charged to charge the charged cloud of particles of active substance. The electric field between the particles and the metallic surface pulls the particles onto the belt and deposits them there.

Further, according to the invention, the active ingredient may be applied to the tape in the form of a solution with a suspension of finely divided drug, ie, a colloidal suspension. The liquid used therefor may 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 jet deposition. In this method, the solution or suspension containing the active ingredient is supplied in metered quantity to a device which sprays a jet of microdroplets concentrated on a particular area of ​​the belt with the aid of a defined area electrostatic field. This method has given very good results when small amounts of active ingredients, for example hormones or enzymes, are to be applied to the tape. With small amounts are called active substances whose normal dose is below 1 mg.

- 16 No. 365449

In addition to the electrostatic spray deposition, certain other coating techniques may be used to load the active ingredient tape which are suitably known in other techniques than for coating a substrate with a liquid. For example, the paper tape can pass under a roller that dips into a bath of saturation liquid. As the belt moves along the roller, the excess fluid is removed by means of another roller, an air jet, a rubber wiper rod, a wire wound rod, ie a Meier rod, or the like. stripped. In this case, the solution penetrates something in the tape, in particular,

Indeed, an object of the invention is to apply the active ingredient to the surface of the belt by the use of a volatile liquid carrier for the active ingredient or by subjecting the belt to heat and / or pressure in its sealing However, closure can penetrate the tape slightly. Simple experiments with these factors, such as volatile liquids, allow to determine the percentage of band-applied active substance that is absorbed in the band. If this parameter is fixed, the on-line test device described here can be adjusted accordingly. When a significant amount of active substance is absorbed in the belt, it is necessary to make up for the outer surface of the dosage unit unloaded belt, ie Band without active ingredient, so that a loss of active ingredient by its exposure to destructive forces, such as air and moisture, is avoided. Obvious modifications of the manufacturing process described later lead to this result.

As already stated, one of the significant advantages of the dosage forms prepared according to the present invention is that pharmaceutically active substance can be made into a stable dosage form without admixing conventional pharmaceutical extractants, which are usually present in conventional solid dosage forms in amounts corresponding to the amount active substance far exceeds. However, there may be a need for small amounts of neutral substance with the active substance according to the invention applied to the bands. For example, when the active substance is applied to the belt in a dry form, a small amount, ie, from about 0 to about 10 weight percent, preferably from about 1/4 to about 2 weight percent of the active substance, of a lubricant be homogeneously mixed. The purpose of this lubricant is to assist the flow of the powdered active substance through the applicator. Suitable lubricants include, for example, fine particulate silicon-containing compositions such as colloidal silica sold under the tradename Cab-O-Sil of Cabot Corp., Boston, Mass., Lime, fine particle starch composition, such as National Starch DriFlo. Ine. u.ähnl. The inclusion of a lubricant and its amount depends on the crystal structure and the flow characteristics of the active substance. In certain cases, a preservative may be added to the active substance. However, when the active substance is applied to the belt in dry form, this is generally not required.

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

The amount of active substance applied to the belt according to the invention varies according to the dosage of the substance, the area of ​​the belt covered, the thickness of the coating and the like. Additional factors affecting the amount of drug applied to the belt are the application method used, the parameters given by the manufacturing process to be described hereinafter, and the type and sensitivity of the on-line testing equipment used. In any event, however, the amount of active substance applied to the tape is such that after preparation and separation of the loaded tape, each resulting form contains a therapeutically effective dosage thereof. As an example of the latter criteria, the thickness of the active substance coating can not exceed 0.005 cm, when the drug uniformity test is performed spectrophotometrically in photon counting technique to measure the ultraviolet absorption of the active substance on the tape. In either case, the amount of active substance applied to the band will be in milligrams or micrograms per centimeter² Band indicated. This is determined for the entire belt area, although it is usually necessary to leave an edge of uncoated belt which is used to seal or seal the dosage form. The ability of the ligaments to absorb active substance according to the invention and to arrange it inside is expressed as a band conversion factor (WCF) and by means of the following

Formula calculated:

the drug exposed surface of the band

- = belt conversion factor maximum area of ​​the finished dosage form

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

15.25 x 1.0.

¹³ - = 30.5 as a band conversion factor.

0.5 χ 1.0

The next step in the preparation of the new dosage forms is the molding or processing stage. As used herein, the term "processing" means converting the ribbon from its initial shape into a solid geometric shape of predetermined shape which is divisible into a plurality of unit dosage forms. This step, like the steps described above, can proceed at high speed in a continuous high speed manufacturing process. This step transforms the flat loaded belt into a shaped geometric shape and generally accommodates the active ingredient substantially within a protective sheet of the belt. The formed band is then singulated and finished so as to give pharmaceutically acceptable unit dosage forms suitable for oral administration.

According to the invention, there are several different processing methods, including extrusion-forming, multi-strip forming, coil-forming, press-forming and the like. be mentioned. The many basic techniques for molding or processing the active substance covered tape are: closed winding, rotary molding, fan-shaped

Wrinkles and layers. These four main techniques are explained in more detail below.

Before discussing the individual processing techniques more closely, the various criteria for an acceptable technique are summarized. The processing or molding technique should allow high speed production and give a geometric shape with high accuracy in terms of uniformity. The process must accommodate the active substance 35 substantially inside the belt. Finally, the processing or forming operation must not exert undue tension on the tapes so that they deform or tear, and must not remove any appreciable amount of active substance from their 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 in the paper converting industry, for example. In spiral winding, paper from different reels is fed to a spiral winding machine, the paper normally being present in windings of 1/2 to 2 cm width. These continuous strips of paper from each roll are wound around a cylindrical mandrel which is supported at one end. The strips are wrapped overlapping. An adhesive is applied to each strip of paper and the overlapping strips form a continuous spiral as they wrap around the mandrel.

- 18 No.365449

Belt turned, which forces the paper roll also forward toward 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. Re-formed paper in this way always has a cavity in its center because of the mandrel on which it is made. When closed winding there is no mandrel, so that in the center of the formed rod, a cavity is neither necessary nor desirable. In fact, the invention expressly intends to severely limit or completely eliminate this central cavity.

FIG. 3 schematically shows an example of closed winding. In this case, the coated or loaded belt -61- is guided by a single roller through the system, which has, for example, guide wires -62- and guide rollers -63- for a cutting arrangement -64- which cuts the tape transversely into desired lengths whose length is usually between about 12 and 25 cm. These pieces of tape are then fed into a corrugating roll assembly in which a corrugating roll forms a series of corrugations by pressing the ribbon against a soft rubber roll. As a result of this corrugation, the individual pieces of tape are formed into loosely wound coils. The loosely wound tapes leaving the corrugating roll assembly then pass between a stationary and a moving surface, wherein the distance between the two surfaces gradually decreases along the trajectory of the wound tapes. The stationary and moving surfaces may be formed as two concentric cylinders, one stationary and the other rotating relative to the stationary cylinder, or, as shown in Fig. 3, in the form of a flat solid plate. be designed as a stationary surface and a moving belt -66-- as a non-stationary surface. When the band pieces formed as loosely wound rods pass between the moving and stationary surfaces, they are tightly wound together until a stable rod is formed. By adjusting the distance between the two surfaces of the rod can be wound together so tightly that any cavity is excluded in its center. If necessary, the distance can be adjusted so that a cavity of desired size remains in the center of the rod ago made.

The rod can be closed or sealed in various ways. First, it has been found that conventional methods, for example sugar gluing, are not suitable for the practice of the invention. In the conventional method, the moving surfaces which come into contact with the belt during rod formation are sprayed or coated with water so as to contact a large area of ​​the belt. The amount of water absorbed by the band, about 18% by weight, is unacceptable in the preparation of the new unit dosage forms because of possible adverse effects on the adhesion of the drug to the band as well as the medicament itself. Furthermore, it has been found that the rods formed by this conventional method are usually too tightly sealed for a good release of the drug in the body. Rather, according to the invention, it has been found that spraying about the same areas of the belt as in the conventional process with a sufficient amount of a fine water spray to moisten the belt only and rapid drying of the bars after their formation yields finished dosage forms which are satisfactory Uniformity and drug release rate, as well as stability with respect to the active ingredient, but with the exception of those drugs which are known to be highly sensitive to moisture in the pharmaceutical preparation.

Second, by placing a piece of heat-sealable edible polymer on the trailing edge of each strip of tape, the bars can be sealed or by coating the trailing edge of each piece with a heat-sealable, edible polymer immediately after being cut from the endless belt , It is also possible to apply a heat-sealable or crosslinkable polymer over the entire length of tape 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. After the rods are tightly wound, they become in this

Nr.365449

Case passed under a heated plate, where the closure takes place by means of heat and pressure. For example, a portion of the solid plate -67- could have a heated area.

The rods can also be sealed after their formation by applying water or an adhesive to the outer layer (s) or tape. Preferably, water is used as the precursor. This process would require the presence of substances in or on the strip material, such as starches or starch derivatives, in the following

Dry or seal with heat or pressure.

The method illustrated by way of example in Fig. 3 uses a jet of water which strikes the outer surface of the endless belt along the lower, returning part thereof so that the belt surface coming into contact with the rolled tape pieces provides a satisfactory flow Seal the rods enough water or water droplets reserves. The water could also be applied to the tightly wound bars by, for example, placing the bars under a water application roller, a porous plate by means of which a metered amount of water is applied uniformly over the entire length of the bars, or a sponge the outer surfaces of the rods applies. The bars could then be passed between another part of the moving and stationary surfaces,

This general method of making the closure by means of water appears over known methods, according to which, as described above, for example, a seal ²⁰ with the help of sugar solution, clearly beneficial. When applying water by the above methods, the total amount of water applied to each bar is smaller than in the prior art methods. As a result, the amount of water removed during the subsequent drying of the bars is substantially smaller than in the known methods.

The rods thus produced are each as long as the width of the tape of the supply roll. 25 A typical width is 20 to 40 cm. After sealing, each rod is moved by means of belt -66- into contact with, for example, ultra-sharp knives -69- (Fig. 3), where it is singulated, ie, where the rod is cut into the desired lengths. The methods for singulating and finishing these rods into finished dosage forms will be explained in more detail below.

A second molding or processing method is commonly referred to as rotary molding. This process can be performed in a number of special ways. It is akin to a general layering process because it initially makes stacks of active substance loaded tape in array of endless strips or bars by fan-folding or laminating, as described further below. In a particular rotary forming process, as shown in Figure 4, a continuous relatively thick multilayer strip of active substance loaded belt -70- is passed between a pair of press rolls 71-. The thus-formed or pressed layered stack -72- is fed to a second station, a bar-forming and compacting station,⁴⁰ continuous rods -74- having a cross-section in the form of a pressed-circle or other desired cross-section is transformed. The rods 74 shaped in the desired geometric shape are passed through a third rotating station where, for example, one or more pairs of correspondingly arranged rollers singulate the bars into individual cans. This can be followed by printing and finishing stages, which are explained in more detail below. The printing process can be done in the separation stage with the third set of rollers -75-.

In the example of rotary forming shown in Fig. 5, the shaped endless stack (strip or rod) 81- is continuously indented at regular intervals by reciprocating die blocks -82- and / or a pair of heated rolls -83-; eingnit50 th, so that in the finished dosage units rounded edges are formed, being discharged from the rotating Dosierformstation a continuous chain at their ends connected dosage units -85-. As with all or the various rotary forming methods of the present invention, the rods modified in this manner are passed through pressure and singulation stations, all of which operate at high speed.

According to another closely related rotary forming technique, the continuous stack is fed to a rotating forming and inspection assembly containing, for example, one or more pairs of stainless steel rolls. The wall layers, which may consist of layers of paper and polymeric film, are heated and pressed into a continuous stack. Preferably, the outer layers of the stack are of paper, for example, to prevent sticking of the stack to the heated rolls. During this densification process, the band plies are joined together to a unit, thereby reducing shifting of the plies and tearing at the edges during subsequent side and end forming operations. Thereafter, the ends of the dosage units are formed, by feeding the continuous rectangular stack formed in the compaction station to a second station, in which the ends of the dosing units are formed by a pair of heated rollers which can have transversely oriented knives on their rolling surfaces. The cut ends of the dosage units are shaped and sealed by the heat from the rolls. The design of the end blade determines the shape of the ends of the dosage units. The shape of the end knives is chosen to provide a smooth transition to the sides of the dosage units which are formed in the next station. which can have at their rolling surfaces transversely oriented knives. The cut ends of the dosage units are shaped and sealed by the heat from the rolls. The design of the end blade determines the shape of the ends of the dosage units. The shape of the end knives is chosen to provide a smooth transition to the sides of the dosage units which are formed in the next station. which can have at their rolling surfaces transversely oriented knives. The cut ends of the dosage units are shaped and sealed by the heat from the rolls. The design of the end blade determines the shape of the ends of the dosage units. The shape of the end knives is chosen to provide a smooth transition to the sides of the dosage units which are formed in the next station.

The sides of the dosage units are formed in the layered formed-end cut material stack by means of a third pair of heated rollers. These rollers can have angled grooves with raised cutting edges. The formation of the grooves in the roll surfaces forms a desired dosage unit cross-section. Heat and pressure acting from the ridge-type cutting elements of the rolls seal the sides of the dosage units to a smooth surface.

The rotary molding process shown in Fig. 5 for the preparation of the dosage units therefore consists of three primary stations, a precompacting station, a final forming station and a side forming station. Each of these stations consists of a set of rollers which are preferably heated and through which the continuous belt stack passes. The formation of the outer surface, ie the peripheral surface, of the rolls is different at each of the stations and depends on the particular station and the desired result. Various additional operations such as additional cutting or separating, printing or finishing stages may be performed between the three stations described. These operations will be described in more detail below.

Within the scope of the invention, one or more of the various stages of the rotary forming process is performed simultaneously and on the endless stratified input strip by means of a single pair of, for example, spring-loaded, heated cooperating rollers, all the various stages discussed above, ie bar formation, dosage formation, singulation and even printing.

The illustrated third example of the rotary forming suggests an example according to which two or more of the stages shown in FIG. 1 are unified. This is illustrated in Fig. 4A, where essentially the layer and rod forming steps of the above-discussed third rotary forming method and also the method of Fig. 4 are combined, for example by the use of a single pair of heated pressing and cutting rollers (not shown in detail). which press the supplied layer assembly simultaneously and cut to a shape that is similar to a side view of several stacked pancakes. These end-cut parts are then fed to a separating device, in which the longitudinal cuts are carried out for producing the individual dosage forms. The compression step, for example, could also be done in this latter station. It is also within the scope of the invention to package the individual dosage forms directly as they result from the singulation process, for example by being inserted in blister packs by means of conventional devices.

A third method of preparing the dosage forms of the invention is the fan folding technique. The fan folding technique could also be classified as a form of layering in the general sense. In this method, first a band of up to, for example, cm width is processed so that the applied active ingredient in its interior on 21

No.365449 is taken. This can be done by first folding the tape in half as well as by laminating two coated tapes together, with the coated surfaces facing each other. A stack of more than one pair of strips laminated in this manner may be used, the strips initially being made, for example, with a greater width of up to 60 cm and being divided after layering so as to form two or more widths in one dimension, as described for fanfold, ie between about 1 and 15 cm.

After the initial folding or stacking of the loaded belt, it is passed between furrow rolls where it is rippled in preparation for the fanfold. The furrow rollers can be driven. Basically, the band is moved by draw rollers. The furrows can be done, for example, that one of the pair of furling rollers is spring loaded. Since the tape preferably folds in the direction of the pinch rings which press into the tape material, the pinch rings may be formed alternately according to the desired fan fold pattern in the upper and lower rollers. The grooved belt then moves into a fan-fold trough with fold tongues which begin to gradually bend the belt at a point of contact and narrow or narrow its width and overlap, so that the band is reasonably firmly folded at the exit end. At the end of the folding trough is a device that pulls the tape through the furrow and folder, such as a pair of spring loaded, powered stainless steel rollers. This fulfills a dual function; the strip is moved through the folding device and the folded strip is compacted into a continuous, solid geometric shape. The pulling device may be combined with the device for closing the band. However, the fan-folded band can be closed by other methods, as explained below. The sealed tapes can be singulated in a variety of ways, as in the rotary forming process described above. which pulls the belt through the furrow and folder, such as a pair of spring loaded, powered stainless steel rollers. This fulfills a dual function; the strip is moved through the folding device and the folded strip is compacted into a continuous, solid geometric shape. The pulling device may be combined with the device for closing the band. However, the fan-folded band can be closed by other methods, as explained below. The sealed tapes can be singulated in a variety of ways, as in the rotary forming process described above. which pulls the belt through the furrow and folder, such as a pair of spring loaded, powered stainless steel rollers. This fulfills a dual function; the strip is moved through the folding device and the folded strip is compacted into a continuous, solid geometric shape. The pulling device may be combined with the device for closing the band. However, the fan-folded band can be closed by other methods, as explained below. The sealed tapes can be singulated in a variety of ways, as in the rotary forming process described above. the strip is moved through the folding device and the folded strip is compacted into a continuous, solid geometric shape. The pulling device may be combined with the device for closing the band. However, the fan-folded band can be closed by other methods, as explained below. The sealed tapes can be singulated in a variety of ways, as in the rotary forming process described above. the strip is moved through the folding device and the folded strip is compacted into a continuous, solid geometric shape. The pulling device may be combined with the device for closing the band. However, the fan-folded band can be closed by other methods, as explained below. The sealed tapes can be singulated in a variety of ways, as in the rotary forming process described above.

Figures 6A-6D illustrate a technique for making a fan-folded dosage form in which the initial fan-folded bands -91- are placed in recesses -92A- of appropriate size of a therapeutically ineffective band structure, preferably of paper and with central strips -92- , This "loaded" central strip, which carries the fan-folded strips, is then sandwiched between outer strips -93- to form a composite, layered structure. This composite endless layered strip is then fed, for example, to a rotating dosage form unit or station which is not dissimilar to the unit -83- of Figure 5 where the strip is placed in the mold of Figure 6B. Thereafter or simultaneously with the according to FIG. 6B processing carried out the separation, which leads to individual dosages according to Figure 6C. Fig. 6D shows the cross section of the dosage form according to Fig. 6C. Fig. 6D shows how the fan-folded bands are fully contained internally, and that the central strip -92- is forced slightly outwardly by the molding process, so that a portion of it is forced between the edges of the outer strips -93- associated with him, exposed. Preferably, the outer strips -93- and the central strip -92- contain no active ingredient, so as to ensure that no active ingredient is present on an outer surface of the individual dosage forms. as the fan-folded bands are completely internally taken up, and that the central strip 92 is forced somewhat outwardly by the molding process, so that a part of it is between the edges of the outer bands which are connected to it; exposed. Preferably, the outer strips -93- and the central strip -92- contain no active ingredient, so as to ensure that no active ingredient is present on an outer surface of the individual dosage forms. as the fan-folded bands are completely internally taken up, and that the central strip 92 is forced somewhat outwardly by the molding process, so that a part of it is between the edges of the outer bands which are connected to it; exposed. Preferably, the outer strips -93- and the central strip -92- contain no active ingredient, so as to ensure that no active ingredient is present on an outer surface of the individual dosage forms.

The fourth basic molding process is "laminating" which has already been generally referred to. In this method, first between about 20 and 60 rolls of tape are simultaneously unwound from a multiple bobbin unwinding station and then brought together to form a continuous bar. The 20 to 60 tape layers may all be made of paper-like material provided with a coating suitable for facilitating sealing in a later stage. They may also consist of a multi-layered arrangement of paper-like tape and heat sealable, edible polymeric tape, or may consist of one or more paper-like layers sandwiched between the alternately heat sealable, edible polymer tapes. Suitable polymeric material is, for example, a water-soluble polyoxyethylene or a cellulose ether derivative with a plasticizer. Any number of bands can be loaded with active substance. Preferably, the bands of paper material are loaded with active substance.

- 22 No.365449

In another method of stacking the active ingredient loaded bands, they are fed directly from the applicator. The width of the band is usually 12 to 25 cm. The roll-mounted or applicator belt may initially be several times the final width, and then slit or slit to the desired final width as part of the stacking process.

Once the belt is stacked, the resulting continuous bundle is fed to a laminating station. For carrying out the invention, known devices can be used which bring strips of flexible films or strips together and produce a laminate from them. As already explained, the application area of ​​active substance on the tape strips or sheets depends, for example, on the method of sealing the laminated body. The cutting and finishing of the composite can also be done differently. For example, laminated bodies can be processed in the rotary mold method described above. The lamination station could also consist of a pair of reciprocating stamping plates which form the dosage forms from the continuously conveyed ribbon stack, seal and cut. A typical stamp plate would have a surface of about 25 χ 25 cm.

In a specific embodiment, the laminates produced according to the invention are distinguished in that they are only sealed 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 having up to 6 layers of paper-like tape interposed between tape layers of a heat-sealable polymeric material in which heat and ink are imparted to the stack in the cutter during singulation Pressure is applied. During singulation, the polymeric tape layers in the stack are deformed and "spread" by the heat and 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 be made of polymeric material. Preferably, the drug is applied to the paper layers of the tape in a paper-polymer tape stack. Such, only at its periphery closed laminated body has a much larger drug release rate than a similar band stack, which is fully laminated.

Another method of making the dosage forms from the ribbon stack is to pass the stack between rotating cylinders that have single dual punches at the outer periphery. The dosage units are formed from the continuously fed ribbon stack, sealed and cut while moving the ribbon stack between such rotating cylinders.

The use of layering techniques as described above brings some advantages in pharmaceutical production. First, the layering technique provides barriers that allow for the incorporation of two or more therapeutically active, incompatible substances without the need to add stablising substances or use a special blending technique, such as the encapsulation of one or more ingredients. Because up to, for example, 60 layers can be used to form a composite, this embodiment of the invention is ideally suited for pharmaceutical preparations with a large number of active substances, where there are numerous possibilities of incompatibilities, for example in multi-vitamin preparations. Furthermore, the insulating effect of the layers of the composite and the deposition of the active substance on the ribbon in the dry state makes this technique ideally suited for the preparation of foaming preparations. In such preparations, the tape material must be such that it readily dissolves or disperses in water. Further, the application of active ingredient to the tape in the dry state is advantageous when the active substance is adversely affected by moisture.

With regard to the stratification, it is further within the scope of the invention to change the composition of the various layers within a layered body as well as to control, oh each layer is covered with active substance. The surface of the uppermost and lowermost layers of a laminated body which are exposed are not coated, whereby the active substance is contained inside. For example, it has been found that interposing sin or multiple layers of starch-based material in a cellulosic composite helps the body to more elasticity than increasing the amount of plasticizer in the composition of the cellulosic sheets.

In the above-mentioned molding method, it is preferred according to the present invention to load the ribbon with active ingredient in wet form when the forming is done by dense wrapping or fan-shaped folding. The rotational shaping and layering methods are suitable for applying active substance in wet or dry form in the same way, the choice depending on the properties of the active ingredient used, for example the solubility in the particular solvent used, the stability to moisture and the like ,

The singulation can not be explained without also explaining the closure 10 and without prior discussion of the processing because, when cutting or separating the shaped ribbons, active ingredient could be exposed on one or more of the outer surfaces. In view of the manufacturing equipment and the need to maintain the integrity of the deposited coating for on-line testing, it is in accordance with the invention essential to apply the active substance continuously to the tape in a sufficient amount so that in the singulation process, dosage forms with one therapeutically effective dose arise. In certain operations described herein, such as fan-shaped folding, the outer edges of the tape may remain free of active substance,

The cutting of the formed band must be performed so that the

Tape is not deformed. The separation process itself can be done by stationary or rotating knives in one or two-stage tools or with other conventional methods. So that the processed strip is not deformed during cutting, different cuts can be made at different angles. Also, as explained above in the rotary forming, the formed strip may be initially slightly flared or scored to compensate for the deformation caused by the high speed singulation.

The formed loaded band can be singulated by a single separation, ie, one unit at a time can be formed by cutting exact lengths of a rod, or, more preferably, several units can be formed simultaneously, for example by using a tightly wound rod using a number evenly spaced cutting edges is divided into several dosage units. Another method for simultaneously producing multiple dosage units would be to use dies which are individually or double and rotatably mounted or mounted reciprocally on plates and sever a multilayer tape or a tightly wound rod-like structure. The shape 35 of the finished dosage form preferably has a pleasing appearance and is such

The shape of the dosage forms produced 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 at its 40 parallel larger sides, so that the ends of the dosage forms cut therewith are approximately rounded. Other modifications will be apparent to those skilled in the art. It should be noted, however, that the processed dosage forms during separation must be supported laterally such that the formation of wrinkles or other irregularities is avoided.

The singulation and the final closure can be combined. For closing or sealing the dosage forms, although there are numerous possibilities, the most common, combined with the possibility of singular is to bring on heat and / or pressure. In addition to sealing the trimmed edges of the dosage form by heating the cutting tool, heat and pressure may be applied to the tool used to bond the laminate. Also, the use of moisture or a volatile solvent to seal the trailing edge of the tightly wound rod discussed above may be extended to the cutting operation by applying such a solvent to the cutting surface. Heat and / or pressure can be used for effective sealing

- 24 Nr.365449 also be applied simultaneously. ,

The methods by which the isolated dosage forms prepared according to the invention can be sealed are not uncommon in the plastics processing and laminating technique. In addition, they include the use of water or volatile solvents such as ethanol, methanol or chloroform, the application of pressure and heat, the application of a separate adhesive, infrared heating, ultrasonic bonding, encapsulation or combinations of these options. A preferred method of sealing dosage forms is the use of a wrapper that can be printed if necessary. Such a wrap may, for example, be a thin layer of edible polymeric material such as hydroxymethylcellulose, 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 by the escape of a volatile solvent. More preferred methods of applying a sealing layer to the discrete dosage units are the encapsulant and the pocket seal.

In the first of these methods, the solid dosage units are passed between mutually approximating sheets of flexible film of, for example, gelatin surrounding the dosage forms as shown in Fig. 6A. The gelatin film is then heat sealed and cut to shape. In the pharmaceutical industry, a device for sipping liquids by means of this method is known. Such a device can be easily rebuilt so that it can be encapsulated with the dosage forms.

A second method is the pocket seal, which can be performed by at least the following two methods. In the first method, preformed pockets of a material such as gelatin or a cellulose derivative are preformed in a device known, for example, in plastic molding, ie injection molding. The singulated 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 above-mentioned bonding methods, for example by ultrasonic welding. The pockets are separated by cutting with a stationary or rotating cutting edge. The walls of the preformed bag are usually thicker than the top or closed position. However, the closed position has sufficient thickness to protect the dosage form. The thickness of the topsheet is such that the dosage form is released from the pouch through the topsheet within a short time after ingestion, usually within a few seconds of reaching the stomach. The bag can also be formed from two identical halves, which are joined together according to the above-mentioned methods.

An alternative to the pocket seal described is the production of a continuous carrier tape or strip from a material as described above for the bags. In this carrier tape holes are punched, which accurately record the dosage forms, for example, fan-shaped folded dosage forms according to Figure 6A. In this embodiment, the singulated dosage forms in the holes are placed, for example, by a pin through the hole and a second pin on top of the singulated dosage form to hold it under pressure. The strip is then sealed by adding a top and back of similar material while maintaining the compression of the dosage units. The thickness of the strip is in no case greater than that of the dosage units. However, the strip may be thinner than the dosage form, but not less than about half the thickness. For several reasons, the carrier strip preferably has about the thickness of the dosage form. First, the sealing film may be as thin as described above in relation to the pocket because it is not significantly deformed in the sealing or bonding process. Second, a thicker carrier tape is less exposed to perforation and singulation. Third, with a thicker strip, the holes can be made more closely adjacent, allowing for minimal waste. When the dosage form is placed in the carrier strip and sealed, the strip will again become as described here, isolated. An advantage of both the bag and the carrier strip concept is that there is strip material on the outer surface, the no

- 25 No.365449 contains active substance and could be subjected to the finishing operations, such as an imprint, a flattening u.ähnl, without causing the risk of loss of active

Substance exists. Also, the use of the bag or carrier strip concept facilitates the use of different colors for the finished dosage form, for example by making the carrier tape, the closure strips or the dosage units themselves in contrasting colors, whereby a pleasing and distinctive appearance can be achieved.

The material used for the manufacture of the bag, the central carrier strip and the abovementioned closure films, like the tapes themselves, must pass precise tests. In addition to the obvious pharmaceutical criteria for purity, good hold, non-toxicity and compatibility with the active ingredient used, the material must have good surface quality, dye and ink receptivity, structural integrity, moldability, dimensional stability and active ingredient release property in water. Preferred substances for this use are hydroxypropyl cellulose and methyl cellulose. A particularly preferred composition comprises hydroxypropyl cellulose, a starch or a starch derivative as an extender and disintegrant, a plasticizer,

One of the greatest advantages afforded by the dosage forms of the present invention is that they are amenable to non-destructive, on-line quality assurance. The off²⁰ Print "non-destructive" is meant here in the practical sense and not exactly literal. By this it is meant that the quality control of the dosage forms occurs during the high speed manufacturing operations, the actual loss being well below 1%. Because the dosage forms can be made with a small standard deviation and corresponding excess excess that is currently standard in the pharmaceutical industry, the very small percentage of dosage lost in testing becomes substantially zero, given the overall tolerances of the dosage takes into account current manufacturing processes.

The dosage forms prepared according to the invention have as finished product the quality assurance of the production process, a concept which is predominant in the pharmaceutical industry. The on-line assays that provide this safety are markedly different from accepted pharmaceutical grade testing procedures, such as chemical and physical control of the constituents of the dosage form prior to manufacture, destroying successful testing of the solid dosage forms upon completion of manufacture for physical characteristics For example, dissolution rates, incidence of the cover u.ähnl., And chemical character³⁵ teristics, such as efficacy, presence of incompatibilities, etc. and physical quality testing of the solid dosage forms, such as manual inspection of bicolor capsules, to ensure that each end has contrasting colors. Such tests, which are recognized and generally practiced in the pharmaceutical industry and described in the official abstracts, have no relationship with an on-line manufacturing control, 40 (ϋθ_ei_n An essential feature of the solid dosage forms prepared according to the invention is, and does not suggest, these too. However, certain conventional methods, such as strict quality control and testing of all ingredients prior to the manufacturing process, form an integral part of the dosage forms described herein, as is common in any proper pharmaceutical manufacturing.

* 5 The on-line quality control of the manufacture of the new dosage forms is provided by the

Fact that all forms described herein are made from a continuous, edible strip which is susceptible to non-destructive testing. First, tape production itself is monitored for physical characteristics of the tape to ensure that the tape is uniform and free of defects. For example, that can

Ribbon are passed through a resonant cavity in which a microwave passing through the belt continuously monitors the ribbon thickness, ie, when a resonant frequency is set, its changes indicate changes in ribbon thickness. Other possibilities of

Monitoring the tape thickness are, for example, the laser beam scattering, a fluid scanning and

- 26 No.365449 directly touching sensors. According to the invention it is also possible, the basis weight of the

Check tape and defects.

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

The above-mentioned methods are applicable both where the tape receives a second coating in the form of one or more additional tapes or where a protective layer is applied to a loaded tape. Laser scanning is particularly advantageous in the on-line quality inspection of such coatings.

A second major field of on-line quality assurance is checking the amount of active substance applied to the belt and checking the uniformity of the application process. It should be recalled here that a significant advantage of the process by which the new dosage forms are prepared is that the active substance is applied to the strip in a form accessible to test methods to be described later, ie in a finely divided manner Shape or as a fine film.

There are various methods for checking the uniformity of the deposition of the active substance. For example, to measure the ultraviolet absorption of a highly absorbing active substance band system, a photon counter can be used. It is also possible to use the absorption of soft X-rays having a wavelength of about 4 Å and beta ray absorption. 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, singulation and finishing stages described above are also suitable for on-line testing as described above with respect to the tape. Such tests, of course, include physical parameters of the tape after processing, such as dimensions, thickness, uniformity and the like. Similar tests may be applied to the individual dosage forms with regard to their shape, uniformity and the like. respectively.

The explanation has hitherto focused primarily on devices with which the dosage units are tested during production on-line and nondestructive. Within the invention, and without departing from the meaning of the term "non-destructive testing", two additional tests are possible.

In a first such operation, a small portion of the tape is periodically removed on-line by severing by means of knives, punches, fluid nozzles or a laser beam. The portion of the removed tape will not destroy the integrity of the tape or adversely affect any processing operations. The tape sample may be removed before or after the active substance is applied or, in some cases, during early stages of processing, for example when some tapes are stacked in a preliminary lay-up or folding operation. The sample thus removed is chemically analyzed for both the band material and the active substance. The analysis is also carried out on a quantitative basis, in particular with regard to the active substance.

In addition to the "stain analysis", samples of the final dosage forms are taken and subjected to on-line property testing. While such testing is currently required on most solid dosage forms available in the US, it is not performed on-line during manufacture as in the invention. First of all, it must be remembered that the dosage forms prepared according to the invention are not subject to batch limitations as a result of their production process. A "batch" may be the number of dosage units that fall between two property specifying samples, provided that the number does not exceed the sampling requirements of the Federal Food and Drug Administration.

A second particular aspect of the property testing of the dosage forms made in accordance with the present invention is that the results of these tests, as well as the other 5 on-line tests discussed herein, can be processed in a computer and used to set the parameters of the manufacturing process. A negative result of any test thus indicates the beginning of a series of production of dosage units that need to be isolated, and the next positive result after corrections automatically ends this series. The dosage units made between these two tests then need to be further tested to see how many are in compliance with the guidelines. Where on-line exams are conducted for example, in terms of the amount of active substance applied, a negative value can be automatically used to simultaneously trigger two functions. First, the tape can be marked with a stain of non-toxic dye, which can temporarily stop the production and manually remove a portion of the tape. Further, the readout via a computer causes an adjustment of the amount of active substance loaded on the belt to increase or decrease the amount to meet the specifications. When the belt passing through the inspection unit returns to specification, a second spot can be automatically applied to the belt, marking the non-conforming belt length. For example, a negative value can be automatically used to trigger two functions simultaneously. First, the tape can be marked with a stain of non-toxic dye, which can temporarily stop the production and manually remove a portion of the tape. Further, the readout via a computer causes an adjustment of the amount of active substance loaded on the belt to increase or decrease the amount to meet the specifications. When the belt passing through the inspection unit returns to specification, a second spot can be automatically applied to the belt, marking the non-conforming belt length. For example, a negative value can be automatically used to trigger two functions simultaneously. First, the tape can be marked with a stain of non-toxic dye, which can temporarily stop the production and manually remove a portion of the tape. Further, the readout via a computer causes an adjustment of the amount of active substance loaded on the belt to increase or decrease the amount to meet the specifications. When the belt passing through the inspection unit returns to specification, a second spot can be automatically applied to the belt, marking the non-conforming belt length. First, the tape can be marked with a stain of non-toxic dye, which can temporarily stop the production and manually remove a portion of the tape. Further, the readout via a computer causes an adjustment of the amount of active substance loaded on the belt to increase or decrease the amount to meet the specifications. When the belt passing through the inspection unit returns to specification, a second spot can be automatically applied to the belt, marking the non-conforming belt length. First, the tape can be marked with a stain of non-toxic dye, which can temporarily stop the production and manually remove a portion of the tape. Further, the readout via a computer causes an adjustment of the amount of active substance loaded on the belt to increase or decrease the amount to meet the specifications. When the belt passing through the inspection unit returns to specification, a second spot can be automatically applied to the belt, marking the non-conforming belt length. Further, the readout via a computer causes an adjustment of the amount of active substance loaded on the belt to increase or decrease the amount to meet the specifications. When the belt passing through the inspection unit returns to specification, a second spot can be automatically applied to the belt, marking the non-conforming belt length. Further, the readout via a computer causes an adjustment of the amount of active substance loaded on the belt to increase or decrease the amount to meet the specifications. When the belt passing through the inspection unit returns to specification, a second spot can be automatically applied to the belt, marking the non-conforming belt length.

²⁰ Similar operations can be performed at all on-line test centers.

Referring to the property analysis, statistical samples of final dosage units can be taken and automatically loaded into any test solutions where their dissolution rate is tested. The specific criteria used to test the dissolution of the unit dosage forms will depend on the active ingredient (s) present. For example, a sample dosing unit may be supplied to a suitable solvent to form a solution of the active ingredient. The resulting test solution can be photometrically scanned to record the concentration of active ingredient as a function of time after the introduction of the test unit. Other possible indicators measured in the test solution include, for example, changes in pg, color, heat, chemical reaction and the like. Devices 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, such as a computer, to adjust the formation, separation, finishing, and sealing operations, as required to correct or improve the measurements.

With the on-line testing methods described here, in all cases, the entire tape can be tested, for example by means of a device that checks the tape thickness. In certain cases, however, an examination of the entire volume may not be advisable for economic reasons. For example, it is possible to test a small band surface by means of a light scattering sensor, and it is further possible to attach two or more sensing devices closely adjacent one another⁴⁰ to sample 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 those cases where only limited strip areas are tested, the testing equipment can be mounted so that it can be moved back and forth across the width of the bar. The percentage of tape and according to the finished dosage units,⁴5 tested in this way far exceeds any current non-destructive testing method in the pharmaceutical industry.

As already mentioned several times, the Fertigbear processing operations for the dosage forms can be performed independently or preferably in combination with other operations, such as singling. 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 vary depending on the Ver used. Depending on whether a closure process takes place, be a problem or not.

- 28 No. 365449

For example, a small irregularity or small edge may be visible where the cutting device comes together when cutting a coated ribbon stack into a particular shape as described above. Also, singulation of the dosage forms prepared by the other preferred processing methods can cause an irregularity at the ends or sides. Overall, however, the processing techniques according to the invention minimize the occurrence of such irregularities.

Irregularities described herein may be removed by light abrasion, 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. This effect must precede printing in most cases.

The surface appearance, ie the gloss of the dosage forms, can range between slightly rough and dull and high gloss, depending on the technique used and the finish desired. When sealing techniques such as bag sealing or encapsulation are used, the gloss of the finished surface can be adjusted by mere selection of the material used to form the seal. The same applies if a sheath is used to seal the dosage forms. In such sealing operations, the irregularities generally do not have to be completely eliminated because the cladding ensures complete continuity of the surface.

The printing process similarly depends on the processing and sealing technique used. The tape itself can be printed at any point in the entire production process. For example, the outer layer of a more coated dosage form may be printed prior to processing as part of the singulation process or even after singulation. Dosage forms made by tight wrapping can still be printed in the contiguous bar or stack. When the dosage forms are sealed by attaching a wrapper, printing is preferably done after applying the wrapper, although the dosage form can be printed and then a clear wrapper can be applied. The printing of solid unit dosage forms before completion of their preparation or mixing,

The selection of a printing method depends on several factors, the most important of which is the physical nature of the substrate to be printed. Selection of a suitable method also depends to some extent on the location throughout the manufacturing process at which printing occurs, that is, whether the tape is printed prior to processing, the finished dosage forms are printed, or printing is at an intermediate location, for example, in combination with other processes, such as singling. The printing method and associated apparatus may 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,

From the foregoing discussion of finishing and printing operations, it can be seen that the color of the dosage forms can be varied in a variety of ways, both in hue and in intensity. First, the ribbon material itself may contain a color that may give an intensity in assembling the ribbon layers during the various processing operations. The color may also result from an envelope or sealing layer. When sealing by means of the bag or encapsulation method, two or more contrasting colors are possible in that the color of the different parts is different. The dosage forms prepared by lamination may have different shapes in that only the color of the tapes supplied to the layer device is different.

The dosage forms which can be prepared according to the invention are with respect to the type of active or

Active substances for which they serve as carriers are not subject to any restrictions. The terms "active substance", "active ingredient" and "drug" used in connection with the 29th

No.365449 finding synonymous to be used throughout the description and