CA1289074C - Process for producing individually dosed administration forms - Google Patents
Process for producing individually dosed administration formsInfo
- Publication number
- CA1289074C CA1289074C CA000525681A CA525681A CA1289074C CA 1289074 C CA1289074 C CA 1289074C CA 000525681 A CA000525681 A CA 000525681A CA 525681 A CA525681 A CA 525681A CA 1289074 C CA1289074 C CA 1289074C
- Authority
- CA
- Canada
- Prior art keywords
- process according
- formulation material
- formulation
- cavity
- blister
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/06—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of pills, lozenges or dragees
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/03—Containers specially adapted for medical or pharmaceutical purposes for pills or tablets
- A61J1/035—Blister-type containers
Abstract
ABSTRACT
Process for producing individually dosed administration forms, in which a carrier material containing active substances plastic at elevated temperature, together with conventional additives is applied to a stationary or moving substrate or introduced into blisters or cavities produced from films and as a result the formulation material is brought into an administration form and a formulation material with a softening point range above the body temperature is heated to above the latter and is dosed under pressure with a viscosity of more than 3,000 mPa.s, together with administration forms obtainable by said process. They can be obtained simply, economically and with good quality.
Process for producing individually dosed administration forms, in which a carrier material containing active substances plastic at elevated temperature, together with conventional additives is applied to a stationary or moving substrate or introduced into blisters or cavities produced from films and as a result the formulation material is brought into an administration form and a formulation material with a softening point range above the body temperature is heated to above the latter and is dosed under pressure with a viscosity of more than 3,000 mPa.s, together with administration forms obtainable by said process. They can be obtained simply, economically and with good quality.
Description
PROCESS FOR PRODUCING INDIVIDUALLY DOS~D ADMINISTRATIO~ FORMS
The invention relates to a process for producing individually dosed administration forms, in which a formulation materia~ which is plastic at elevated temperature and contains active agents and conventional additives is placed on a stationary or moving substrate or in blisters or cavities produced from films, the formulation material is transferred, and then cooled, into the administration Eorm, as well as to the administration forms obtained by this process.
The conventional, widely used, solid administration forms for the administration of medicaments, dietetics and the like are essentially tablets dragees, soft and hard gelatin capsules~ These administration forms all require in a first stage shaping and in a second stage product packaging, which must meet the requirements of the product (e.g. stability) and the wishes of the consumer (e.g. attractiveness).
The stepwise production oE a product up to the final packaging is disadvantageous from the cost standpoint when it is possible to obtain usable products no longer requiring separate shaping and instead are given their particular shape by the packaging or as a result o~ the consistency thereof through si~ple, dosing application to a substrate "run" to the desired shape and are then solidiEied. If simpler ways are possible, two-stage procedures are disadvantageous.
It could be assumed that processes for filliny forms are known and widely used and no longer have any novelty value. As ~k . 1~
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-la- 26835-14 will be shown hereinafter, patents contain information on this subject, which also applies to the pharmaceutical field.
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. . - 2 -. DE-AS 1 017 322 describes a pr~eess in which use is made of a combined mould and pack for moulding and despatching ready for sRle and use blanks of medicaments and similar materia].s, such as . suppositorie~, pastil]es and the like. ~owever, two or more hinged-interconnected mould parts are required, each of which : must have more than half the thickness of the subsequent moulded , ~
part to be effecti~e in the sense of the known proposal. It is not possible to separate a packed :individual dose.
The entire length of the sliding cover must be removed from the pack to permit the requisite folding apart of the mould parts for remo~ing the shaped blanks. This necessarily leads to a contamination of the fragment~ which have remained in the pack due to dirt and microorganisms. DE-AS 1 017 322 also mentions the filling of the mould parts ~ith the aid of a moulding frame, which is intended to permit a filling of the mould up to the edge.
Material which projects and then solidifies after moulding can be scraped off and reused. This filling process cannot be pharmaceutically relevant as a re~ult of its do~ing inaccuracy, beoause the medicaments resulting therefrom would not meet pre~en,tday demands.
, The sarne applie~ with regards to the proposal for producing packaged admini~tration forms accord.ing to German patent 1 947 684.
f Thi~ proposal constitute~ a further development of the prior art of DE-AS 1 017 322, in that the aforementioned mouldins frame is replaced by a perforated film, which is intended to en~ure cleaner fllling of the individual mould~. Here a~ain it is a complex, ,1~ , ,.
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, , 2683~-14 discontinuous and hygenically dubious procedure, which cannot therefore be satisfactory.
The procedure o~ moulding fat-containing materials has been further developed in the meantime. Thus, for some time, separatable hollow forms or cavities preshaped from films have been filled with melted suppository material. A~ter passing through a cooling tunnel, the previously open form is sealed.
Approxirnately 25,000 suppositories per hour can be produced by using costly, automated machines. It is a disadvantage of this process, which is limited to fats with melting points below 40C, that solid substances may sediment during the moulding and cooling process due to the low viscosity of the melted fat. Another danger is the possible change to the physical parameters of t~e fats used due to melting and recooling. There can be mel-ting point changes and the n~oulded articles may become brittle.
Attempts have been made to apply the knowledge acquired in connection with moulding oE suppositories to orally administrable dosage forms. Thus, DE-OS 27 lO 307 describes a process for producing and packaging solid pharmaceutical dosage units in tablet form, wherein the mixture is applied to a continuously moving belt made from a different material and having tablet-like depressions. The carrier substance can be constituted by fats, atty mixtures, as well as o~her liquid substances and components, whose meltiny point is above 37C and preferably above ~3C. An important statement of DE-OS 27 10 307 for the purposes of the present invention is that the melted mixture of carrier substance and active component is "poured" into the depressions `: ~
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with or without a measuring device. This can only mean that it is a low-viscosity, liquified substance mixture which can still be poured, whilst the risk of sedimentation of solids is inherent therein and leads to limitations with respect to the carrier substances used.
The description of the process of DE-OS 27 10 307 does not extend beyond the use of relatively low-melting fats and waxes, which can serve as a matrix for the active substance or substances. It is left open as to how these products can be removed without breaking from the depressions of the foils, how they taste as fats and what release rates are to be expected. ~t least no product is as yet known which has achieved marXet success.
The knowledge of the aforementioned pa~ent literature and related publications reveals that the results have not been satisfactory. Firstly the use of carrier substances is limi~ed to those materials which, as fats or waxes, have a relatively low melting point and secondly the introdu~tion of the material into the moulds is limited to pouring processes.
On the basis of this prior art, according to the present invention, it is attempted to develop a method by which it i5 possible to process more advantageous matrix materials than those described in DE-OS 27 10 307 and which are highly viscous at temperatures above body temperature and have viscosity values of more than 3000 mPa.s, in a simple and economic manner to high-quality, individually dosed administration ~orms, without the :- : : . . .
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- 5 - ~7998-2 aforementioned, dlsadvantageou~ sedlmentatlon tendency of suspended components.
Thus the present lnventlon provides a process for producing indlvidually separated oral administration dosage unlt forms of a formulation material. The formulation material contains at least one active substance and a formulation base which comprises (a) a gel forming substance and (b) at least one normally liquid gel formation aid selected from the group consisting of water, an organic solvent and a plasticizer. The formulation material is plastic or sol at an elevated temperature and is an elas~ic and break-proof gel at room temperature and has a sol/gel phase transition point above the body temperature. The process comprises~
heatlng the formulation ma~erial above ~he sol/gel phas~
transition temperature in a heating tank suah that the formulat~on material becomes sol having a viscosity of 3,000 to 500,000 mPa.s;
transferring the war~ formulation material from the heating tank into a heated dosing apparatus operated at a high pressure and provlded with a controlled compressed air valva which provides precise opening and closing within the time of milliseconds and against which a uniform high pressure of 2 to 160 bar is applied by a piston or geared pump;
dischargin0 under the uniform pressure and at such a temperature that the viscoslty of the warm formulation remains at least 3,000 mPa.s, a constant quantity of the warm formulation material through a precisely time-limited opening/closing of the valve onto a stationary or moving substrate or into a blister or cavity pack made of f ilm~ and : . .
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- 6 - 2799~-2 cooling the formulatlon material below the ~ol/gel phase transition point, th~reby produciny the dosage uni~ form w.i~hou~
using a shaping element and solely as a result of the temperature and the vl~coslty of the formulation material.
Another aspect of the present invention provides an individually dosed adminlstration forms macle of a thermoplastic formulatlon material with a softening point above body temperature, produced by the process mentioned above.
An essential feature of the invention is that the formulation material to be processed has a sof~ening point (i.e., sol/gel phase transition polntJ above the body temperature. Thus, the formulation material has the nature of a thermoplastic or plaster. Thus, in essence, these materials are not permanently shapeable at ~ormal ~emperature. Thus, these materials can be hard or even brittle at normal temperature, but can reversibly soften when heated and can be mechanically relatively easlly shaped in order to ultimately pass lnto the state of a vlscou~ materlal at higher temperatures. It is al~ays neceæsary to fulfil the requirement of the invention that the formulation material has a softening range above the body temperature. It is obv~ous that this requirement or ~haracteristic of the thermoplastlc material islessentlally determined by the carrier material to be described in grehter detail hereinafter. However, addltive~, such as plastlcizing additives and the ll~e also have an influence thereon. It is a further requirement of the invention that the minlmum viscosity of the carrier material iB 3000 mPa.s at the processin~ temperature.
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However, this viscosity value can be greatly exceeded, e.g. up to more -than 50,000 mPa.s or even more than 100,000 m~a.s and can extend up to 500,000 mPa.s.
The process according to the invention can be particularly successfully performed with dosing equipment capable of managing viscosities o~ up to 500,000 mPa.s, because it is not possible to use simple pumping and pouring processes.
The present invention may be better understood re~erring to the accompanying drawings, in which:
Figure 1 through 3, show examples of a variety of shapes of the dosage unit forms and shapes of their cavities which can be produced or employed according to the present invention; and Figure 4 shows a schematic view of an apparatus which can be used for carrying out the process according to the present invention.
An equipment used for carrying out the process of the present invention, may have heatable units operating at high pressure, which have controllable valves, against which a piston or geared pumps build up a uniform high pressure. Through a time-precisely limited opening of the ~alve, a constant quantity of the formulation material is discharged. Incorporated nozzles or filling needles ensure a clean filling of the hollow forms/cavities and blisters or an exact application to the substrates. The pressure under which the dosage unit formation ta~es place is generally above 2 bar and i9 dependent on the viscosity of the heated formulation ~aterial. The pressure is ~2~ 7~
preferably be~ween 10 and 70 bar, partlcularly between 35 and 55 bar.
Basic equipments of the presently described type of filling plants are supplied, for example, by the ~irms P]anatol-Werk or Gerhards-Dosiertechnik and are illustrated by Fig. 4. Components of such equipments include a heatable preheating and heating tank 1, from which the warm material is brought into heatable high pressure hoses 3 with the aid of geared pumps 2 projecting into the tank and under regulatable pressure and bypass control. The equipment can have one or more outlets for hose connections. The pressure in the hoses can be up to 160 bar. The hoses are connected to heatable dosing heads 4, which are equipped with spring-mounted ball valves and nozzles 5. By using a controlled compressed air valve, opening and closing cycles calculated in milliseconds are obtained and as a function of the pressure upstream of the valve, the same amount of material is always discharged Eor the same pressures and opening times.
Any cobwebbing of the materials can be prevented by different noz,zle sizes and temperature changes at the dosing heads. In addition to nozzles constructed as injection needles, it is also ; possible to use conical, double and multiple, as welI as surface nozzles. Regulating and control electronics 6 ensure the monitoring and respecting of predetermined pressure and temperature values. By means of synchronizing circuitary the speed of the geared pumps and a belt carrying the for~s can be matched to one another.
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In order to completely fulfil the purposes of the present invention, modiEications can be made to the basic equipment, which make it possible to arrange the injection heads in such a way that there can be several injection shots per form on the forms sliding by. The can also be installed in movable manner, so that charge samples can be taken or analytical purposes, e.g. for determining the homo~eneity of the charge or the injection shot weight.
As several injection heads may be simultaneously used and controlled by a central unit it is easily possible to fill 100,000 or more dosage unit forms per hour. The output rate i5 limited only by the mechanical advance of the cavities or forms and each individual nozzle can perform more than 1,000 cycles per minute. Thus, this type of filling system permits a much higher output rate than the equipment hitherto used for the filling of preshaped cavities or forms.
The dosing accuracy of the injection heads can be checked by separate removal from the filling line and saparate injection into a weighing dish. In an experimental run for a production rate of 70,000 filled deep drawn cavities per hour with a Eilling weight of 500 mg, an accuracy of less than plus/minus 2%
and a relative standard deviation of less than 1~ were found.
Laetus equipment, which checks each dosage unit form Eor precise filling, can be used for a continual inspection during the filling process. It is also possible to pass the sealed strips over a +
balance.
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As a result of the above-described procedure according to the present invention, it is possible to process a highly concentrated solution or suspension of an active substance with a small amount of a carrier substance, whilst filling can still take place with great accuracy. In the case of highly ViSCOllS
solutions or suspensions, the aforementioned sedimentation tendency is largely eliminated. The filling equipment makes it possible to process materials with viscosities above 500,000 mPa.s. Thus, individual dosage forms of small, space-saving type which are easy to swallow are obtained.
With the aid of the aforementioned dosing procedu~e, it is possible to produce dosage forms, which in the simples~ case can be injection moulded without any mould on a substrate, either cooled, at ambient temperature or heated to above this and either stationary or in moving form. The viscosity and temperature of the materials to be processed then determine the shape of the desired article. This either leads to flat "lonzenges" with a tablet-like appearance or cap-shaped products. If the substrate, e.g. a conveyor belt, moves during the injection process, then small bars or strips are obtained. By simultaneously moving the spraying head in difEerent directions, e.g. with the aid of an eccentric disk, a great variety of product shapes are obtained and which can e.g. assume the shape of internal organs, such as the heart or stomach and in this way can refer to the particular indication range of the product produced (see E'ig. 1~.
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~ 26835-14 Logically following the principle of the present invention, an embodiment of the process involves filling blister packs with the molten formulation materials. Blisters packs or "cupules" are drawn out of foils or films of various type and these are filled and seaLed with a cover film or foil, which is generally made of coated alumimium. The enclosed formulation material is pressed by the cover foil and is consequently available. The process according to the present invention also makes it possible to produce many different shapes and sizes of different administration forms (see Fig. 2). Appropriately t~e blisters are given a slightly conical shape to facilitate the pressing out of the product.
The process according to the present invention may be most advantageously carried out by thP filling of hollow forms or cavities, i.e. dosage unit forms of any shape and size which are closed all round, except for a feed funnel.
For producing these cavities, it is possible to use essentially any commerically available shapeable and sealable films and foils, provided that they are compatible with the content to be introduced. Particuarly suitable are thermoplastic resins, ; such as preferahly polyethylene-coated polyvinyl chloride (PVC), polypropylene (PP) or polyvinylidenechloride (PVDC) films, and plastic-coated aluminium foils, provided that they can be shaped to the desired hollow form. It is also possible to use papers coated with plastics. Special colours or coatings of the films can make the enclosed product light, moisture or oxidation-proof.
The films can be printed or marked in some other way for : '' ' . ~
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iden-tifying the product. The term "films" is intended to cover all materials which can be used for the present purpose of forming hollow forms or cavities from films, i.e. apart from plastic films, also metal foils as well as coated paper and cardboard materials and the like.
Numerous different procedures can be used for producing the cavities. The subsequently described processes are only preferred examples. IJsing moulds, symmetrical or asymmetrical half-caivties can be p~oduced from two films, which are welded together in a tight manner at their edges. Initially a funnel-shaped opening is left in the upper part of the cavity and is used for introducing the formulation material. The opening is sealed in conventional manner following the filling process and this gives an all round tight pack. Shaping and filling can be performed in such a way that the individual packs are attached in the form of several "strips", from which the user can separate an individual dose. The product placed in the cavity is exposed by tearing apart of the films.
In individual cases, it can be particularly advantageous if the films have a small, unsealed area, in which one film projects over the other by a few millimetres. This projection makes'it easier to separate the films.
The individual cavities can be provided with constricted areas, which permit a subsequent division, i.e. portioning of the product, e.g. for a child's dose or portions of a solid article for a three times daily dose (see for example, Fig. 3, the third form from the top).
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The procedure according to the present invention for producing shaped blanks without any mould-dependent shaping and filling of blister packs and preshaped hollow forms is no~
described including the substances and formulation materials, which are entirely different from the known suppository formulations or the materials given in ~E-OS 27 10 307. In addition, vital advantages of the invention compared with the known administration Eorms will be explained~
Whereas the charges for illing suppository forms or those according to DE-OS 27 10 307 are preferably fats, having a relatively low melting point, according to the process of the present invention, suitable substances for basic formulations can be raw materials belonging to gel forming agents. When heated, these gel forming agents form sols with water, other solvents and/or plasticizers. Dissolving of the gel forming agents can take place at temperatures above 100C. Further adjuvants and active substances can be incorporated, generally by kneading into the cooled solution. At ambient temperature, the viscosity is generally between 50,000 and 800,000 mPa.s.
The articles obtained with the aid of the described dosing equipment are elastic, break-proof and suitable for swaliowing, sucking, chewing or Eor buccal or perlingual application. They do not melt fats at body temperature and instead decompose or dissolve in the body fluids at a planned varying speed. If water is used for mixing purposes, this can either be left in the formulations or the articles can be dried to 3~
-13a- 26835-14 a certain moisture content, e.g. in air conditioning cabinets, so that the hardness and elasticity can be controlled.
As a function of the solubility of the adjuvants and active substances, there are dif~ering, controllable releases of the active substances, whilst there can be considerable variations as regards the nature and quantity of the adjuvants. This makes it possible to easily produce articles with a marked retarding action.
A particularly preferable administration form obtainable according to the invention is a product which is resistant to the gastric juices. By incorporating into the basic formulations, a substance or substance mixtures which do not dissolve in gastric juice, or through the exclusive use of such substance or substance mixtures, it is possible to obtain products capable of withstanding the gastric juice resistance tests given in pharmacopeias.
The administration forms of the present invention also ~ake it possible to produce products, in which the initial dose and retard form are in one dose. A special example o~ this is constituted by the soporific chloral hydrate, which is a rapidly, but briefly acting hypnotic. To make it unnecessary for the patient to take this medicament twice or more during the evening or night and so as to permit uniform deep sleep, it is desirable to guarantee a roughly eight hour sleeping period by a single does during the evening, without hangover effect the following morning.
Thus, according to the invention two or three chloral hydrate-containing formulations with different release : . ; . , - '~ ~' ' ' .
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~13b- 26835-14 characteristics can be produced and successively injected in superimposed manner into the hollow form or cavity. The product then looks like that of Fig. 3a and the diEferent layers can be made clear, for example by diEferent colours of the individual formulations. A furthex development of this idea is the processing of fundamentally incompatible substance combinations, such as vitamin-mineral mixtures. The first injection shot introduces a vitamin formulation, the second a neutral formulation as a protective coating and finally the third shot introduces a mineral formulation giving an identical ..~.,~,, ,. : .
~ ~ -layer effect to that of Fig. 3a. It is obvious that the basic form~lations in this case must coalesce to give a single solid article. It was pointed out hereinbefore that no difficulties arise when arranging the lndividual injection heads of the filling system for such injection sequences. It is obvious that the information given in connec-tion with the above example is to be considerecl in ge~eral terms, i.e. for producing layered administration forms according to the invention.
Products suit,able for buccal or sublingual administration can be produced in ~any different forms and compositions according to the basic principle of the invention, Thus, for example, spherical bodies with a small surface or elongated strips with a large surface can be shaped. Readily soluble or almost insoluble substances or mixtures can be used for producing the medicament, as a function of the desired residence time in the mouth. An important advantage of the invention is that slimy substances can be processed, which adhere for a long -time to the mucous membrane of the mouth ancl consequently permit close eontact with the mucous membranes of t~e active substance to be applied.
A further possibility of use of the present invention is the procluction of chewing and suclcing articles, whose solubility can fluc hlate between fast and llchewing gum-lilce~. It is e.g. possible to embed substances, which are known as mouth and throat disinfectants or astringents, or as breatll frasllellers. It is also possible to embed in the basic formulation insoluble substances, which have a certain abrasive effect ~nd sarve to .
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clean the teeth when chewing. Chewable antacids, which as viscous suspensions are attached to the mucous rnembranc of the stomach in film-forming manner, constitute a further field of use of the chewing products obtainable according to the invention. In this example the superiority of the administration forms of the present invention become partic~larly apparent. The hither-to known chewable antacids were constituted by tablets, which disintegrated in crumbling manner during chewing. The individual particles irritate the throat leading to coughing. In the case oP the forms according to the invention, a viscous suspension forms in the mouth and which can be swallowed without irritating the mucous membranes.
';', According to the invention it is also possible to fill emulsions, e.g. of the W/O or O/W t~pe, which decompose in the presence of body juices to finelyi disposed droplets and consequently facilitate the resorption of oils and fats and substances possibly dissolved therein. Naturally these emulsions ~ust solidify below approximately 40 C in order to be able to remove them from the ca~ities.
'. ' The invention also makes it possible to add to the dosage forms to be produced substances which are necessary for ensurin~ or obtaining a special pH or HLB value. The substances can e.g. be buffer mixtures or emulsifiers with a specific HLB value.
Unlike in the case of gelatin capsules, in which the filling with enzymes is problematical, these can easily be processed in , .
the products obtainable according to the invention, because there is no need to use coatings or adjuvants which are attacked by the enzymes and which therefore reduce enxyme activity.
Another advantage of the invention is that the processing of oily substances, normally reserved for soft gelatin capsules, is readily possible by applying the oil to a carrier.
This mixture is then injected together with a gel forming agent to give cavities which have no tendency to "bleed" or leak. This makes it possible to also process aqueous solutions, which is not conceivable for hard and soft capsule fillings.
It is not claimed that the above list of possible uses ~or the administration forms is complete and it can in fact be C extended at random. Specific statement~are to be considered in general terms in the sense of the invention.
The following substances and representatives of substance classes or carrier materials can be advantageousLy used according to the present invention: albumins, gelatins, casein, plant proteins, zein, lecithins, agar, gum Arabic, pectins, alginates, xanthan, natural and modified starches, maltodextrin, methyl cellulose, ethyl cellulose, cellulose ether polysaccharide 5, carboxymethyl celluloses, etherified carboxymethyl celluloses, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phtalate, polyvinylacetate, polyvinylacetate phthalate, polyinylalcohol, polyvinylpyrrolidone, polyacrylic acid, methacrylic acid and methacrylate polymers, polyethylene glycols, polyoxyethylene-polyoxypropylene polymers ~Poloxalcol*), Trade M~rk , :` ' .
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triglycerides, partial glyceride mixtures, ethoxylated partial glycerides, long-chain fatty acids and their salts, silicones, colloidal silicic acid, bentonites, etc.
Substances usuable as plasticizers are e.g. glycerol, propylene glycol, polyethylene glycols, acetyltributyl citrate, triacetin, dibutyl tartrate, dibutyl phthalate, sorbitol, sorbitan mixtures, glucose syrup, etc.
For reasons of completeness it is pointed out that it is also possible to add other additives, such as e.g. opacifiers, dyes~ flavours, sweeteners, preservatives and the like.
It is important for the invention that the aforemen-~ tioned materials are so matched in preparing a formulation ; material that the adhesion between the solidified formulation material and the internal surface of the hollow form or cavity is reduced to a minimum. In most cases standard thermoplastics and carriers or formulation masses permit a clean separation.
However~ if this is not possible in individual cases, the invention provides advantageous aids, to which reference will be made hereinafter.
If necessary, it is possible according to the inventionto provide the cavities with release coatings prior to the filling with the formulation material, in order to prevent sticking or adhesion between the film surface and the formulation material or at least reduce it to a minimum. Pre~erably the formulation material/release agent pairs have the affinity pairs lipo-philic/lipophobic or hydrophilic/hydrophobic. Preferred substan-ces for this purpose are e.g. talc, starches and the like. It is also possible to atomize or spray into the cavity separating ~2~t~
-18- 26835-~4 agents, such as oils, fats or silicones. E'inally such substances can also be applied to the inner wall by using brush-like, rotary tools, which spread within the cavity. The same applies with respect to deep-drawn packs.
I-t can be advantageous to apply the release agent to one side of the starting film prior to the removal of the hollow cavity and said prepared side subsequently forms the inner surface of the cavity.
However, the above-described coating procedures also make it possible to apply those coatings to the inner wall of the cavity which do not function as a release medium, but instead serve as a carrier coating for lubricantæ or dyes, ilavours, sweeteners, preservatives and the like and which inter alia favourably influence the application or administration of the product. This carrier coating is joined to the introduced formu-lation material and is placed like a jacket round the solid article. This ensures that only the outer coating of the product is e.g. coloured or aromatized, which greatly reduces corrigents, which would otherwise have to be homogeneously distributed in much larger quantities in the complete charge.
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- 19 _ The invention clearly leads to many advantages. Thus, it permits the cost~saving and environmentally bene-ficial production of orally usable administration forms not suffering from the disadvan-tages referred to hereinbefore~ Thus, inexpensive produc-ts are made available, ~hich can be readily produced in very large numbers. It is possible to use an almost unlimited number of different formulations for different indications.
Inherently incompatible substances can be present in a single administration form without reacting with one another. It is also possible to process side by side and in large numbers adjuvants, such as e.g. solid and liquid substances which influence the solubility of an active agent, so that plann-ed active substance releases are brought about.
~' The description of the in~entive process makes it clear that the obligatory shaping process for many administration forms is rendered superfluous, because the pack simultaneously forms the shaping elemen-t. Thus, there are no packaging problems with respect to the supply of the objects to the packaging machines or with respect to dimensional tolerances, such as have been hitherto unavoidable in the case of soft gelatin cap~ules.
There is no possibility of intermixing of "foreign bodies", such as ~oreisn dragees or capsules, such as can occur in the hitherto known processes during production or packaging, because the product is introduced directly in thc liquid st~te into the pack and the ~illing opening is sealed. By special shaping of the ~ilm, form and content, it is possible to exclude confusion with respect to the products.
. , - 20 _ The invention also makes it possible to process a very large number of substances side by side, i.e. adjuvants or active substances on the one hand, or solid and liquid substances on the other. This can lead to products with a controlled active substance release, as well as to gastric juice-resi~tant products. It is also possible to produce che~ing and sucking articles.
Many of the novel products, to the extent that they are not designed as sucking or gastric juice~resistant products, as they are generally elastic, can be bit and swallowed irl small fragments, without it being necessary to subsequently drink a liquid, which is a help in the case of patients having swallowing difficulties or who do not like to take tablets.
The invention also provides man~ economic advantages. Thus, the separate shaping stage is obviated, which in itself greatly reduces costs compared with knowrl processes. Th~ high output rate of filled and therefore simultaneously packed forms per time unit and the easily installed on-line process controls represent a further cost-saving rationalization~ To the extent that the inventive process i9 also suitable as a substitute for all known conventional capsule production methods, it is possible to obviate the costs ~or expensive airconditioning plants and installations f`or recovering solvents~ Since, unlike in capsule production, no raw material is wasted (approximately 50% wastase in sof`t capsule production and approximately 30/0 in hard c~psule product~on), thi~ also leads to a clear savin~.
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Finally, the inventive process can be performed without prejudice to the environment.
The fo~lowing examples Eurther illustrate the inven-tion.
Various types of carriers can be combined in various w~ys for different use purposes. The multiplicity of possibil-ities of the process can only be intimated by the examples.
Example 1 Gelatin 120 g 70% sorbitol solution 180 g Water 373 g Water-soluble protein hydrolyzate 600 g Sorbic acid 5 g Caramel 12 g Meat extract flavour ~
1300 g The gelatin is dissolved in vacuo at 70C in the solu-tion of sorbic acid in water. The flavour, caramel, sorbitol solution and protein hydrolyzate are successively incorporated into this solution. The mixture is vented under heat. At 56C
and 48 bar, the material is injected or atomized into heaps of in each case 1300 mg on a substrate cooled to 10C. Drying takes place at 20% relative humidity and ambient temperature until each individual dose weighs 1090 mg.
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Example 2 Decomposed, esterified starch (Emgum) 120 g Oxidized whea-t starch (Emox)180 g Susar 5o g 75% glucose syrup 175 g Water 200 g Chlorhexidine 6 g Extractum Arnicae plv. subt~10 g Citric acid:sodium citrate 1:1 20 g Ginger flavour 7 g 760 g The sugar, glucose syrup and water are heated to 110C until a clear solution is obtained, Both starch types are introduced, accompanied by vigorous stirring, into the solution cooled to 70C~ The mixture is briefly heated to 90 C. After cooling again to 70 C, the remaining substances are homogeneously incorporated in the rising order of their weights. At 70C
and 90 bar and with a dosing head temperature of 85C, the material is injected into blisters with a tablet-lilse depression. Each dose contains 750 mg. Sealing takes place with a peel-off film.
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Cardiac glycoside 0.5 g ethoxylated partial glyceride mi~ture of ~atural, saturated, even-numbered 100.0 g plant fatty acids (Softigen 767) * Trade ~ark , r ~ ~ .
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' : ' ~ 7~ 26835-14 Polyoxye-thylene-polyoxypropylene polymer tPoloxalcol) 700.0 g Polyethylene glycol 400 (PEG) 199.5 g 1000.0 g Accompanied by moderate stirring, the melted Poloxalcol kept at 60C is introduced into the PEG heated to 60C. The solution of card:iac glycoside .in Soft:igen heated tol~5C is homogeneously st:irred into the first so:luti.on. The material cooled to ~5C
is injected in 200 mg quantities at 22 bar in-to oval cavities cooled to lO C. The cooled cavities can immediately be sealed.
Gelatin 2~0 g llydroxypropyl-methyl-cellulose phthalate (HP 55) 90 g W~ter 389 g 25% ammonia Zl g 85% glycerol 260 g ; looo g The homogeneous powder miXt~lre of Selatin and HP 55 is rapidly introduced, accompanied by stirring, into the mixture o-f water and ammonia. It is important for all the po~e~er particles to be uni~ormly wetted. ~ollowing a swelling time of 12 minutcs at am~ion-t temporat~Lre, the crumbly materinl is meltod in vncuo at 90C. Tho glycerol heated to l~0C is stirred into the * Trade Mark , .~
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- 24 _ viscous material obtained. The cooled material is a basic material for a gastric juice-resistant a~ministration form.
By dying the material during production, e.g~ with erythrosine, . , it is possible to show that dosed portions are resistant for 2 hours to artificial gastric juice (O.ln HCl) without hleeding, whilst after -transfer into a buffer solution (0.2 m Na2HP04 ~_ solution 77~ ml ~ 0.1 m citric acid solution 227 ml; pH 6.8), they dissol~e uniformly and without leaving a residue ~ithin 26 minutes.
By incorporating filling material~ e.g. corn starch into the basic formulation the ga~tric juice resistance is retained, whilst the solubility in artificial intestinal juice can be controllably extended to se~eral hours.
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Gelatin 240 g Cellulose-acetate phthalate ~CAP) 90 g Water 410 g 85% glycerol Z60 g : : 1000 g This formulation is prepared in the same wa~ as example 4 ancl the beha~iour o~ the dosed portions correspond to those of examp1e 4, ;'',' ' ' . .
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Example 6 Polyvinylpyrrolidon (PVP) (Kollidon*30) 50 g Oxidized starch (Emox 170) 250 g o5% glycerol 250 g Water 230 g Maltodextrin 480 g Diphenhydramine-~lCl 10 g ~ennel-honey flavour . lO g 1280 g 'The water and glycerol are mixed. The PVP is introduced into the cold solution and stirred until completely dissolved.
Accompanied by stirring, -the maltodextrin is firstly dissolved in the solution heated to 95C, followed by the stirring ln of the starch~ also at g5C. The diphenhydramine and the fla~our are homogeneously incorporated into the mixture cooled to 75C. The material is filled in 1280 mg portions into blisters at 65 to 70C and 95 bar and immediately after ~he olidification of the ma-terial they are sealed with peel-off film.
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The invention relates to a process for producing individually dosed administration forms, in which a formulation materia~ which is plastic at elevated temperature and contains active agents and conventional additives is placed on a stationary or moving substrate or in blisters or cavities produced from films, the formulation material is transferred, and then cooled, into the administration Eorm, as well as to the administration forms obtained by this process.
The conventional, widely used, solid administration forms for the administration of medicaments, dietetics and the like are essentially tablets dragees, soft and hard gelatin capsules~ These administration forms all require in a first stage shaping and in a second stage product packaging, which must meet the requirements of the product (e.g. stability) and the wishes of the consumer (e.g. attractiveness).
The stepwise production oE a product up to the final packaging is disadvantageous from the cost standpoint when it is possible to obtain usable products no longer requiring separate shaping and instead are given their particular shape by the packaging or as a result o~ the consistency thereof through si~ple, dosing application to a substrate "run" to the desired shape and are then solidiEied. If simpler ways are possible, two-stage procedures are disadvantageous.
It could be assumed that processes for filliny forms are known and widely used and no longer have any novelty value. As ~k . 1~
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-la- 26835-14 will be shown hereinafter, patents contain information on this subject, which also applies to the pharmaceutical field.
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. . - 2 -. DE-AS 1 017 322 describes a pr~eess in which use is made of a combined mould and pack for moulding and despatching ready for sRle and use blanks of medicaments and similar materia].s, such as . suppositorie~, pastil]es and the like. ~owever, two or more hinged-interconnected mould parts are required, each of which : must have more than half the thickness of the subsequent moulded , ~
part to be effecti~e in the sense of the known proposal. It is not possible to separate a packed :individual dose.
The entire length of the sliding cover must be removed from the pack to permit the requisite folding apart of the mould parts for remo~ing the shaped blanks. This necessarily leads to a contamination of the fragment~ which have remained in the pack due to dirt and microorganisms. DE-AS 1 017 322 also mentions the filling of the mould parts ~ith the aid of a moulding frame, which is intended to permit a filling of the mould up to the edge.
Material which projects and then solidifies after moulding can be scraped off and reused. This filling process cannot be pharmaceutically relevant as a re~ult of its do~ing inaccuracy, beoause the medicaments resulting therefrom would not meet pre~en,tday demands.
, The sarne applie~ with regards to the proposal for producing packaged admini~tration forms accord.ing to German patent 1 947 684.
f Thi~ proposal constitute~ a further development of the prior art of DE-AS 1 017 322, in that the aforementioned mouldins frame is replaced by a perforated film, which is intended to en~ure cleaner fllling of the individual mould~. Here a~ain it is a complex, ,1~ , ,.
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, , 2683~-14 discontinuous and hygenically dubious procedure, which cannot therefore be satisfactory.
The procedure o~ moulding fat-containing materials has been further developed in the meantime. Thus, for some time, separatable hollow forms or cavities preshaped from films have been filled with melted suppository material. A~ter passing through a cooling tunnel, the previously open form is sealed.
Approxirnately 25,000 suppositories per hour can be produced by using costly, automated machines. It is a disadvantage of this process, which is limited to fats with melting points below 40C, that solid substances may sediment during the moulding and cooling process due to the low viscosity of the melted fat. Another danger is the possible change to the physical parameters of t~e fats used due to melting and recooling. There can be mel-ting point changes and the n~oulded articles may become brittle.
Attempts have been made to apply the knowledge acquired in connection with moulding oE suppositories to orally administrable dosage forms. Thus, DE-OS 27 lO 307 describes a process for producing and packaging solid pharmaceutical dosage units in tablet form, wherein the mixture is applied to a continuously moving belt made from a different material and having tablet-like depressions. The carrier substance can be constituted by fats, atty mixtures, as well as o~her liquid substances and components, whose meltiny point is above 37C and preferably above ~3C. An important statement of DE-OS 27 10 307 for the purposes of the present invention is that the melted mixture of carrier substance and active component is "poured" into the depressions `: ~
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with or without a measuring device. This can only mean that it is a low-viscosity, liquified substance mixture which can still be poured, whilst the risk of sedimentation of solids is inherent therein and leads to limitations with respect to the carrier substances used.
The description of the process of DE-OS 27 10 307 does not extend beyond the use of relatively low-melting fats and waxes, which can serve as a matrix for the active substance or substances. It is left open as to how these products can be removed without breaking from the depressions of the foils, how they taste as fats and what release rates are to be expected. ~t least no product is as yet known which has achieved marXet success.
The knowledge of the aforementioned pa~ent literature and related publications reveals that the results have not been satisfactory. Firstly the use of carrier substances is limi~ed to those materials which, as fats or waxes, have a relatively low melting point and secondly the introdu~tion of the material into the moulds is limited to pouring processes.
On the basis of this prior art, according to the present invention, it is attempted to develop a method by which it i5 possible to process more advantageous matrix materials than those described in DE-OS 27 10 307 and which are highly viscous at temperatures above body temperature and have viscosity values of more than 3000 mPa.s, in a simple and economic manner to high-quality, individually dosed administration ~orms, without the :- : : . . .
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- 5 - ~7998-2 aforementioned, dlsadvantageou~ sedlmentatlon tendency of suspended components.
Thus the present lnventlon provides a process for producing indlvidually separated oral administration dosage unlt forms of a formulation material. The formulation material contains at least one active substance and a formulation base which comprises (a) a gel forming substance and (b) at least one normally liquid gel formation aid selected from the group consisting of water, an organic solvent and a plasticizer. The formulation material is plastic or sol at an elevated temperature and is an elas~ic and break-proof gel at room temperature and has a sol/gel phase transition point above the body temperature. The process comprises~
heatlng the formulation ma~erial above ~he sol/gel phas~
transition temperature in a heating tank suah that the formulat~on material becomes sol having a viscosity of 3,000 to 500,000 mPa.s;
transferring the war~ formulation material from the heating tank into a heated dosing apparatus operated at a high pressure and provlded with a controlled compressed air valva which provides precise opening and closing within the time of milliseconds and against which a uniform high pressure of 2 to 160 bar is applied by a piston or geared pump;
dischargin0 under the uniform pressure and at such a temperature that the viscoslty of the warm formulation remains at least 3,000 mPa.s, a constant quantity of the warm formulation material through a precisely time-limited opening/closing of the valve onto a stationary or moving substrate or into a blister or cavity pack made of f ilm~ and : . .
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- 6 - 2799~-2 cooling the formulatlon material below the ~ol/gel phase transition point, th~reby produciny the dosage uni~ form w.i~hou~
using a shaping element and solely as a result of the temperature and the vl~coslty of the formulation material.
Another aspect of the present invention provides an individually dosed adminlstration forms macle of a thermoplastic formulatlon material with a softening point above body temperature, produced by the process mentioned above.
An essential feature of the invention is that the formulation material to be processed has a sof~ening point (i.e., sol/gel phase transition polntJ above the body temperature. Thus, the formulation material has the nature of a thermoplastic or plaster. Thus, in essence, these materials are not permanently shapeable at ~ormal ~emperature. Thus, these materials can be hard or even brittle at normal temperature, but can reversibly soften when heated and can be mechanically relatively easlly shaped in order to ultimately pass lnto the state of a vlscou~ materlal at higher temperatures. It is al~ays neceæsary to fulfil the requirement of the invention that the formulation material has a softening range above the body temperature. It is obv~ous that this requirement or ~haracteristic of the thermoplastlc material islessentlally determined by the carrier material to be described in grehter detail hereinafter. However, addltive~, such as plastlcizing additives and the ll~e also have an influence thereon. It is a further requirement of the invention that the minlmum viscosity of the carrier material iB 3000 mPa.s at the processin~ temperature.
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However, this viscosity value can be greatly exceeded, e.g. up to more -than 50,000 mPa.s or even more than 100,000 m~a.s and can extend up to 500,000 mPa.s.
The process according to the invention can be particularly successfully performed with dosing equipment capable of managing viscosities o~ up to 500,000 mPa.s, because it is not possible to use simple pumping and pouring processes.
The present invention may be better understood re~erring to the accompanying drawings, in which:
Figure 1 through 3, show examples of a variety of shapes of the dosage unit forms and shapes of their cavities which can be produced or employed according to the present invention; and Figure 4 shows a schematic view of an apparatus which can be used for carrying out the process according to the present invention.
An equipment used for carrying out the process of the present invention, may have heatable units operating at high pressure, which have controllable valves, against which a piston or geared pumps build up a uniform high pressure. Through a time-precisely limited opening of the ~alve, a constant quantity of the formulation material is discharged. Incorporated nozzles or filling needles ensure a clean filling of the hollow forms/cavities and blisters or an exact application to the substrates. The pressure under which the dosage unit formation ta~es place is generally above 2 bar and i9 dependent on the viscosity of the heated formulation ~aterial. The pressure is ~2~ 7~
preferably be~ween 10 and 70 bar, partlcularly between 35 and 55 bar.
Basic equipments of the presently described type of filling plants are supplied, for example, by the ~irms P]anatol-Werk or Gerhards-Dosiertechnik and are illustrated by Fig. 4. Components of such equipments include a heatable preheating and heating tank 1, from which the warm material is brought into heatable high pressure hoses 3 with the aid of geared pumps 2 projecting into the tank and under regulatable pressure and bypass control. The equipment can have one or more outlets for hose connections. The pressure in the hoses can be up to 160 bar. The hoses are connected to heatable dosing heads 4, which are equipped with spring-mounted ball valves and nozzles 5. By using a controlled compressed air valve, opening and closing cycles calculated in milliseconds are obtained and as a function of the pressure upstream of the valve, the same amount of material is always discharged Eor the same pressures and opening times.
Any cobwebbing of the materials can be prevented by different noz,zle sizes and temperature changes at the dosing heads. In addition to nozzles constructed as injection needles, it is also ; possible to use conical, double and multiple, as welI as surface nozzles. Regulating and control electronics 6 ensure the monitoring and respecting of predetermined pressure and temperature values. By means of synchronizing circuitary the speed of the geared pumps and a belt carrying the for~s can be matched to one another.
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In order to completely fulfil the purposes of the present invention, modiEications can be made to the basic equipment, which make it possible to arrange the injection heads in such a way that there can be several injection shots per form on the forms sliding by. The can also be installed in movable manner, so that charge samples can be taken or analytical purposes, e.g. for determining the homo~eneity of the charge or the injection shot weight.
As several injection heads may be simultaneously used and controlled by a central unit it is easily possible to fill 100,000 or more dosage unit forms per hour. The output rate i5 limited only by the mechanical advance of the cavities or forms and each individual nozzle can perform more than 1,000 cycles per minute. Thus, this type of filling system permits a much higher output rate than the equipment hitherto used for the filling of preshaped cavities or forms.
The dosing accuracy of the injection heads can be checked by separate removal from the filling line and saparate injection into a weighing dish. In an experimental run for a production rate of 70,000 filled deep drawn cavities per hour with a Eilling weight of 500 mg, an accuracy of less than plus/minus 2%
and a relative standard deviation of less than 1~ were found.
Laetus equipment, which checks each dosage unit form Eor precise filling, can be used for a continual inspection during the filling process. It is also possible to pass the sealed strips over a +
balance.
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As a result of the above-described procedure according to the present invention, it is possible to process a highly concentrated solution or suspension of an active substance with a small amount of a carrier substance, whilst filling can still take place with great accuracy. In the case of highly ViSCOllS
solutions or suspensions, the aforementioned sedimentation tendency is largely eliminated. The filling equipment makes it possible to process materials with viscosities above 500,000 mPa.s. Thus, individual dosage forms of small, space-saving type which are easy to swallow are obtained.
With the aid of the aforementioned dosing procedu~e, it is possible to produce dosage forms, which in the simples~ case can be injection moulded without any mould on a substrate, either cooled, at ambient temperature or heated to above this and either stationary or in moving form. The viscosity and temperature of the materials to be processed then determine the shape of the desired article. This either leads to flat "lonzenges" with a tablet-like appearance or cap-shaped products. If the substrate, e.g. a conveyor belt, moves during the injection process, then small bars or strips are obtained. By simultaneously moving the spraying head in difEerent directions, e.g. with the aid of an eccentric disk, a great variety of product shapes are obtained and which can e.g. assume the shape of internal organs, such as the heart or stomach and in this way can refer to the particular indication range of the product produced (see E'ig. 1~.
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~ 26835-14 Logically following the principle of the present invention, an embodiment of the process involves filling blister packs with the molten formulation materials. Blisters packs or "cupules" are drawn out of foils or films of various type and these are filled and seaLed with a cover film or foil, which is generally made of coated alumimium. The enclosed formulation material is pressed by the cover foil and is consequently available. The process according to the present invention also makes it possible to produce many different shapes and sizes of different administration forms (see Fig. 2). Appropriately t~e blisters are given a slightly conical shape to facilitate the pressing out of the product.
The process according to the present invention may be most advantageously carried out by thP filling of hollow forms or cavities, i.e. dosage unit forms of any shape and size which are closed all round, except for a feed funnel.
For producing these cavities, it is possible to use essentially any commerically available shapeable and sealable films and foils, provided that they are compatible with the content to be introduced. Particuarly suitable are thermoplastic resins, ; such as preferahly polyethylene-coated polyvinyl chloride (PVC), polypropylene (PP) or polyvinylidenechloride (PVDC) films, and plastic-coated aluminium foils, provided that they can be shaped to the desired hollow form. It is also possible to use papers coated with plastics. Special colours or coatings of the films can make the enclosed product light, moisture or oxidation-proof.
The films can be printed or marked in some other way for : '' ' . ~
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iden-tifying the product. The term "films" is intended to cover all materials which can be used for the present purpose of forming hollow forms or cavities from films, i.e. apart from plastic films, also metal foils as well as coated paper and cardboard materials and the like.
Numerous different procedures can be used for producing the cavities. The subsequently described processes are only preferred examples. IJsing moulds, symmetrical or asymmetrical half-caivties can be p~oduced from two films, which are welded together in a tight manner at their edges. Initially a funnel-shaped opening is left in the upper part of the cavity and is used for introducing the formulation material. The opening is sealed in conventional manner following the filling process and this gives an all round tight pack. Shaping and filling can be performed in such a way that the individual packs are attached in the form of several "strips", from which the user can separate an individual dose. The product placed in the cavity is exposed by tearing apart of the films.
In individual cases, it can be particularly advantageous if the films have a small, unsealed area, in which one film projects over the other by a few millimetres. This projection makes'it easier to separate the films.
The individual cavities can be provided with constricted areas, which permit a subsequent division, i.e. portioning of the product, e.g. for a child's dose or portions of a solid article for a three times daily dose (see for example, Fig. 3, the third form from the top).
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The procedure according to the present invention for producing shaped blanks without any mould-dependent shaping and filling of blister packs and preshaped hollow forms is no~
described including the substances and formulation materials, which are entirely different from the known suppository formulations or the materials given in ~E-OS 27 10 307. In addition, vital advantages of the invention compared with the known administration Eorms will be explained~
Whereas the charges for illing suppository forms or those according to DE-OS 27 10 307 are preferably fats, having a relatively low melting point, according to the process of the present invention, suitable substances for basic formulations can be raw materials belonging to gel forming agents. When heated, these gel forming agents form sols with water, other solvents and/or plasticizers. Dissolving of the gel forming agents can take place at temperatures above 100C. Further adjuvants and active substances can be incorporated, generally by kneading into the cooled solution. At ambient temperature, the viscosity is generally between 50,000 and 800,000 mPa.s.
The articles obtained with the aid of the described dosing equipment are elastic, break-proof and suitable for swaliowing, sucking, chewing or Eor buccal or perlingual application. They do not melt fats at body temperature and instead decompose or dissolve in the body fluids at a planned varying speed. If water is used for mixing purposes, this can either be left in the formulations or the articles can be dried to 3~
-13a- 26835-14 a certain moisture content, e.g. in air conditioning cabinets, so that the hardness and elasticity can be controlled.
As a function of the solubility of the adjuvants and active substances, there are dif~ering, controllable releases of the active substances, whilst there can be considerable variations as regards the nature and quantity of the adjuvants. This makes it possible to easily produce articles with a marked retarding action.
A particularly preferable administration form obtainable according to the invention is a product which is resistant to the gastric juices. By incorporating into the basic formulations, a substance or substance mixtures which do not dissolve in gastric juice, or through the exclusive use of such substance or substance mixtures, it is possible to obtain products capable of withstanding the gastric juice resistance tests given in pharmacopeias.
The administration forms of the present invention also ~ake it possible to produce products, in which the initial dose and retard form are in one dose. A special example o~ this is constituted by the soporific chloral hydrate, which is a rapidly, but briefly acting hypnotic. To make it unnecessary for the patient to take this medicament twice or more during the evening or night and so as to permit uniform deep sleep, it is desirable to guarantee a roughly eight hour sleeping period by a single does during the evening, without hangover effect the following morning.
Thus, according to the invention two or three chloral hydrate-containing formulations with different release : . ; . , - '~ ~' ' ' .
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~13b- 26835-14 characteristics can be produced and successively injected in superimposed manner into the hollow form or cavity. The product then looks like that of Fig. 3a and the diEferent layers can be made clear, for example by diEferent colours of the individual formulations. A furthex development of this idea is the processing of fundamentally incompatible substance combinations, such as vitamin-mineral mixtures. The first injection shot introduces a vitamin formulation, the second a neutral formulation as a protective coating and finally the third shot introduces a mineral formulation giving an identical ..~.,~,, ,. : .
~ ~ -layer effect to that of Fig. 3a. It is obvious that the basic form~lations in this case must coalesce to give a single solid article. It was pointed out hereinbefore that no difficulties arise when arranging the lndividual injection heads of the filling system for such injection sequences. It is obvious that the information given in connec-tion with the above example is to be considerecl in ge~eral terms, i.e. for producing layered administration forms according to the invention.
Products suit,able for buccal or sublingual administration can be produced in ~any different forms and compositions according to the basic principle of the invention, Thus, for example, spherical bodies with a small surface or elongated strips with a large surface can be shaped. Readily soluble or almost insoluble substances or mixtures can be used for producing the medicament, as a function of the desired residence time in the mouth. An important advantage of the invention is that slimy substances can be processed, which adhere for a long -time to the mucous membrane of the mouth ancl consequently permit close eontact with the mucous membranes of t~e active substance to be applied.
A further possibility of use of the present invention is the procluction of chewing and suclcing articles, whose solubility can fluc hlate between fast and llchewing gum-lilce~. It is e.g. possible to embed substances, which are known as mouth and throat disinfectants or astringents, or as breatll frasllellers. It is also possible to embed in the basic formulation insoluble substances, which have a certain abrasive effect ~nd sarve to .
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clean the teeth when chewing. Chewable antacids, which as viscous suspensions are attached to the mucous rnembranc of the stomach in film-forming manner, constitute a further field of use of the chewing products obtainable according to the invention. In this example the superiority of the administration forms of the present invention become partic~larly apparent. The hither-to known chewable antacids were constituted by tablets, which disintegrated in crumbling manner during chewing. The individual particles irritate the throat leading to coughing. In the case oP the forms according to the invention, a viscous suspension forms in the mouth and which can be swallowed without irritating the mucous membranes.
';', According to the invention it is also possible to fill emulsions, e.g. of the W/O or O/W t~pe, which decompose in the presence of body juices to finelyi disposed droplets and consequently facilitate the resorption of oils and fats and substances possibly dissolved therein. Naturally these emulsions ~ust solidify below approximately 40 C in order to be able to remove them from the ca~ities.
'. ' The invention also makes it possible to add to the dosage forms to be produced substances which are necessary for ensurin~ or obtaining a special pH or HLB value. The substances can e.g. be buffer mixtures or emulsifiers with a specific HLB value.
Unlike in the case of gelatin capsules, in which the filling with enzymes is problematical, these can easily be processed in , .
the products obtainable according to the invention, because there is no need to use coatings or adjuvants which are attacked by the enzymes and which therefore reduce enxyme activity.
Another advantage of the invention is that the processing of oily substances, normally reserved for soft gelatin capsules, is readily possible by applying the oil to a carrier.
This mixture is then injected together with a gel forming agent to give cavities which have no tendency to "bleed" or leak. This makes it possible to also process aqueous solutions, which is not conceivable for hard and soft capsule fillings.
It is not claimed that the above list of possible uses ~or the administration forms is complete and it can in fact be C extended at random. Specific statement~are to be considered in general terms in the sense of the invention.
The following substances and representatives of substance classes or carrier materials can be advantageousLy used according to the present invention: albumins, gelatins, casein, plant proteins, zein, lecithins, agar, gum Arabic, pectins, alginates, xanthan, natural and modified starches, maltodextrin, methyl cellulose, ethyl cellulose, cellulose ether polysaccharide 5, carboxymethyl celluloses, etherified carboxymethyl celluloses, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phtalate, polyvinylacetate, polyvinylacetate phthalate, polyinylalcohol, polyvinylpyrrolidone, polyacrylic acid, methacrylic acid and methacrylate polymers, polyethylene glycols, polyoxyethylene-polyoxypropylene polymers ~Poloxalcol*), Trade M~rk , :` ' .
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triglycerides, partial glyceride mixtures, ethoxylated partial glycerides, long-chain fatty acids and their salts, silicones, colloidal silicic acid, bentonites, etc.
Substances usuable as plasticizers are e.g. glycerol, propylene glycol, polyethylene glycols, acetyltributyl citrate, triacetin, dibutyl tartrate, dibutyl phthalate, sorbitol, sorbitan mixtures, glucose syrup, etc.
For reasons of completeness it is pointed out that it is also possible to add other additives, such as e.g. opacifiers, dyes~ flavours, sweeteners, preservatives and the like.
It is important for the invention that the aforemen-~ tioned materials are so matched in preparing a formulation ; material that the adhesion between the solidified formulation material and the internal surface of the hollow form or cavity is reduced to a minimum. In most cases standard thermoplastics and carriers or formulation masses permit a clean separation.
However~ if this is not possible in individual cases, the invention provides advantageous aids, to which reference will be made hereinafter.
If necessary, it is possible according to the inventionto provide the cavities with release coatings prior to the filling with the formulation material, in order to prevent sticking or adhesion between the film surface and the formulation material or at least reduce it to a minimum. Pre~erably the formulation material/release agent pairs have the affinity pairs lipo-philic/lipophobic or hydrophilic/hydrophobic. Preferred substan-ces for this purpose are e.g. talc, starches and the like. It is also possible to atomize or spray into the cavity separating ~2~t~
-18- 26835-~4 agents, such as oils, fats or silicones. E'inally such substances can also be applied to the inner wall by using brush-like, rotary tools, which spread within the cavity. The same applies with respect to deep-drawn packs.
I-t can be advantageous to apply the release agent to one side of the starting film prior to the removal of the hollow cavity and said prepared side subsequently forms the inner surface of the cavity.
However, the above-described coating procedures also make it possible to apply those coatings to the inner wall of the cavity which do not function as a release medium, but instead serve as a carrier coating for lubricantæ or dyes, ilavours, sweeteners, preservatives and the like and which inter alia favourably influence the application or administration of the product. This carrier coating is joined to the introduced formu-lation material and is placed like a jacket round the solid article. This ensures that only the outer coating of the product is e.g. coloured or aromatized, which greatly reduces corrigents, which would otherwise have to be homogeneously distributed in much larger quantities in the complete charge.
, .
;
.
~8~ 7~
. .
- 19 _ The invention clearly leads to many advantages. Thus, it permits the cost~saving and environmentally bene-ficial production of orally usable administration forms not suffering from the disadvan-tages referred to hereinbefore~ Thus, inexpensive produc-ts are made available, ~hich can be readily produced in very large numbers. It is possible to use an almost unlimited number of different formulations for different indications.
Inherently incompatible substances can be present in a single administration form without reacting with one another. It is also possible to process side by side and in large numbers adjuvants, such as e.g. solid and liquid substances which influence the solubility of an active agent, so that plann-ed active substance releases are brought about.
~' The description of the in~entive process makes it clear that the obligatory shaping process for many administration forms is rendered superfluous, because the pack simultaneously forms the shaping elemen-t. Thus, there are no packaging problems with respect to the supply of the objects to the packaging machines or with respect to dimensional tolerances, such as have been hitherto unavoidable in the case of soft gelatin cap~ules.
There is no possibility of intermixing of "foreign bodies", such as ~oreisn dragees or capsules, such as can occur in the hitherto known processes during production or packaging, because the product is introduced directly in thc liquid st~te into the pack and the ~illing opening is sealed. By special shaping of the ~ilm, form and content, it is possible to exclude confusion with respect to the products.
. , - 20 _ The invention also makes it possible to process a very large number of substances side by side, i.e. adjuvants or active substances on the one hand, or solid and liquid substances on the other. This can lead to products with a controlled active substance release, as well as to gastric juice-resi~tant products. It is also possible to produce che~ing and sucking articles.
Many of the novel products, to the extent that they are not designed as sucking or gastric juice~resistant products, as they are generally elastic, can be bit and swallowed irl small fragments, without it being necessary to subsequently drink a liquid, which is a help in the case of patients having swallowing difficulties or who do not like to take tablets.
The invention also provides man~ economic advantages. Thus, the separate shaping stage is obviated, which in itself greatly reduces costs compared with knowrl processes. Th~ high output rate of filled and therefore simultaneously packed forms per time unit and the easily installed on-line process controls represent a further cost-saving rationalization~ To the extent that the inventive process i9 also suitable as a substitute for all known conventional capsule production methods, it is possible to obviate the costs ~or expensive airconditioning plants and installations f`or recovering solvents~ Since, unlike in capsule production, no raw material is wasted (approximately 50% wastase in sof`t capsule production and approximately 30/0 in hard c~psule product~on), thi~ also leads to a clear savin~.
' ~
, 7~
Finally, the inventive process can be performed without prejudice to the environment.
The fo~lowing examples Eurther illustrate the inven-tion.
Various types of carriers can be combined in various w~ys for different use purposes. The multiplicity of possibil-ities of the process can only be intimated by the examples.
Example 1 Gelatin 120 g 70% sorbitol solution 180 g Water 373 g Water-soluble protein hydrolyzate 600 g Sorbic acid 5 g Caramel 12 g Meat extract flavour ~
1300 g The gelatin is dissolved in vacuo at 70C in the solu-tion of sorbic acid in water. The flavour, caramel, sorbitol solution and protein hydrolyzate are successively incorporated into this solution. The mixture is vented under heat. At 56C
and 48 bar, the material is injected or atomized into heaps of in each case 1300 mg on a substrate cooled to 10C. Drying takes place at 20% relative humidity and ambient temperature until each individual dose weighs 1090 mg.
~:.
' ' ' ~Z~9~
Example 2 Decomposed, esterified starch (Emgum) 120 g Oxidized whea-t starch (Emox)180 g Susar 5o g 75% glucose syrup 175 g Water 200 g Chlorhexidine 6 g Extractum Arnicae plv. subt~10 g Citric acid:sodium citrate 1:1 20 g Ginger flavour 7 g 760 g The sugar, glucose syrup and water are heated to 110C until a clear solution is obtained, Both starch types are introduced, accompanied by vigorous stirring, into the solution cooled to 70C~ The mixture is briefly heated to 90 C. After cooling again to 70 C, the remaining substances are homogeneously incorporated in the rising order of their weights. At 70C
and 90 bar and with a dosing head temperature of 85C, the material is injected into blisters with a tablet-lilse depression. Each dose contains 750 mg. Sealing takes place with a peel-off film.
i xame~
Cardiac glycoside 0.5 g ethoxylated partial glyceride mi~ture of ~atural, saturated, even-numbered 100.0 g plant fatty acids (Softigen 767) * Trade ~ark , r ~ ~ .
-' ' ' ' ~
' : ' ~ 7~ 26835-14 Polyoxye-thylene-polyoxypropylene polymer tPoloxalcol) 700.0 g Polyethylene glycol 400 (PEG) 199.5 g 1000.0 g Accompanied by moderate stirring, the melted Poloxalcol kept at 60C is introduced into the PEG heated to 60C. The solution of card:iac glycoside .in Soft:igen heated tol~5C is homogeneously st:irred into the first so:luti.on. The material cooled to ~5C
is injected in 200 mg quantities at 22 bar in-to oval cavities cooled to lO C. The cooled cavities can immediately be sealed.
Gelatin 2~0 g llydroxypropyl-methyl-cellulose phthalate (HP 55) 90 g W~ter 389 g 25% ammonia Zl g 85% glycerol 260 g ; looo g The homogeneous powder miXt~lre of Selatin and HP 55 is rapidly introduced, accompanied by stirring, into the mixture o-f water and ammonia. It is important for all the po~e~er particles to be uni~ormly wetted. ~ollowing a swelling time of 12 minutcs at am~ion-t temporat~Lre, the crumbly materinl is meltod in vncuo at 90C. Tho glycerol heated to l~0C is stirred into the * Trade Mark , .~
~2 ~9 ~i 7~
- 24 _ viscous material obtained. The cooled material is a basic material for a gastric juice-resistant a~ministration form.
By dying the material during production, e.g~ with erythrosine, . , it is possible to show that dosed portions are resistant for 2 hours to artificial gastric juice (O.ln HCl) without hleeding, whilst after -transfer into a buffer solution (0.2 m Na2HP04 ~_ solution 77~ ml ~ 0.1 m citric acid solution 227 ml; pH 6.8), they dissol~e uniformly and without leaving a residue ~ithin 26 minutes.
By incorporating filling material~ e.g. corn starch into the basic formulation the ga~tric juice resistance is retained, whilst the solubility in artificial intestinal juice can be controllably extended to se~eral hours.
xarnple ~
Gelatin 240 g Cellulose-acetate phthalate ~CAP) 90 g Water 410 g 85% glycerol Z60 g : : 1000 g This formulation is prepared in the same wa~ as example 4 ancl the beha~iour o~ the dosed portions correspond to those of examp1e 4, ;'',' ' ' . .
.' ~: .
- .
~ .
~ : . . . : . .: :
:
:
Example 6 Polyvinylpyrrolidon (PVP) (Kollidon*30) 50 g Oxidized starch (Emox 170) 250 g o5% glycerol 250 g Water 230 g Maltodextrin 480 g Diphenhydramine-~lCl 10 g ~ennel-honey flavour . lO g 1280 g 'The water and glycerol are mixed. The PVP is introduced into the cold solution and stirred until completely dissolved.
Accompanied by stirring, -the maltodextrin is firstly dissolved in the solution heated to 95C, followed by the stirring ln of the starch~ also at g5C. The diphenhydramine and the fla~our are homogeneously incorporated into the mixture cooled to 75C. The material is filled in 1280 mg portions into blisters at 65 to 70C and 95 bar and immediately after ~he olidification of the ma-terial they are sealed with peel-off film.
.
* Trade Mark .
.
.
Claims (21)
1. A process for producing individually separated oral administration dosage unit forms of a formulation material which contains at least one active substance and a formulation base that comprises (a) a gel-forming substance and (b) at least one gel formation aid being liquid at normal temperature and being selected from the group consisting of water, an organic solvent and a plasticiser, the formulation material being plastic or sol at an elevated temperature and being an elastic and break-proof gel at room temperature and having a sol/gel phase transition point above the body temperature, which process comprises:
heating the formulation material above the sol/gel phase transition point in a heating tank such that the formulation material becomes plastic having a viscosity of 3,000 to 500,000 mPa.s;
transferring the warm formulation material from the heating tank into a heated dosing apparatus operated at a high pressure and provided with a controlled compressed air valve which provides precise opening and closing cycles within the time of milliseconds and against which a uniform high pressure of 2 to 160 bar is applied by a piston or geared pump;
discharging, under the uniform pressure and at such a temperature that the viscosity of the warm formulation remains at least 3,000 mPa.s, a constant quantity of the warm formulation material through a precisely time-limited opening/closing of the valve onto a stationary or moving substrate or into a blister or cavity pack made of a film; and cooling the formulation material below the sol/gel phase transition point, thereby producing the administration dosage unit form without using a shaping element and solely as a result of the temperature and the viscosity of the formulation material.
heating the formulation material above the sol/gel phase transition point in a heating tank such that the formulation material becomes plastic having a viscosity of 3,000 to 500,000 mPa.s;
transferring the warm formulation material from the heating tank into a heated dosing apparatus operated at a high pressure and provided with a controlled compressed air valve which provides precise opening and closing cycles within the time of milliseconds and against which a uniform high pressure of 2 to 160 bar is applied by a piston or geared pump;
discharging, under the uniform pressure and at such a temperature that the viscosity of the warm formulation remains at least 3,000 mPa.s, a constant quantity of the warm formulation material through a precisely time-limited opening/closing of the valve onto a stationary or moving substrate or into a blister or cavity pack made of a film; and cooling the formulation material below the sol/gel phase transition point, thereby producing the administration dosage unit form without using a shaping element and solely as a result of the temperature and the viscosity of the formulation material.
2. The process according to claim 1, wherein:
the gel-forming agent is at least one member selected from the group consisting of albumins, gelatins, casein, plant proteins, zein, lecithin, agar, gum Arabic, pectins, alginates, xanthin, natural and modified starches, maltodextrin, methyl cellulose, ethyl cellulose, cellulose ether polysaccharides, carboxymethyl celluloses, etherified carboxymethyl celluloses, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, polyvinylacetate, polyvinylacetate phthalate, polyvinylalcohol, polyvinylpyrrolidone, polyacrylic acid, methacrylic acid and methacrylate polymers, polyethylene glycols, polyoxyethylene-polyoxypropylene polymers, triglycerides, partial glyceride mixtures, ethoxylated partial glycerides, long-chain fatty acids and their salts, silicones, colloidal silicic acid and bentonite; and the gel formation aid is at least one member selected from the group consisting of water, glycerol, propylene glycol, polyethylene glycols, acetyltributyl citrate, triacetin, dibutyl tartrate, dibutyl phthalate, sorbitol, sorbitan mixtures and glucose syrup.
the gel-forming agent is at least one member selected from the group consisting of albumins, gelatins, casein, plant proteins, zein, lecithin, agar, gum Arabic, pectins, alginates, xanthin, natural and modified starches, maltodextrin, methyl cellulose, ethyl cellulose, cellulose ether polysaccharides, carboxymethyl celluloses, etherified carboxymethyl celluloses, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, polyvinylacetate, polyvinylacetate phthalate, polyvinylalcohol, polyvinylpyrrolidone, polyacrylic acid, methacrylic acid and methacrylate polymers, polyethylene glycols, polyoxyethylene-polyoxypropylene polymers, triglycerides, partial glyceride mixtures, ethoxylated partial glycerides, long-chain fatty acids and their salts, silicones, colloidal silicic acid and bentonite; and the gel formation aid is at least one member selected from the group consisting of water, glycerol, propylene glycol, polyethylene glycols, acetyltributyl citrate, triacetin, dibutyl tartrate, dibutyl phthalate, sorbitol, sorbitan mixtures and glucose syrup.
3. The process according to claim 1, wherein the gel-forming agent is at least one member selected from the group consisting of gelatin, water-soluble protein hydrolyzate, natural or modified starch, polyoxyethylene polyoxypropylene copolymer, hydroxy - propyl - methyl - cellulose phthalate, cellulose-acetate phthalate, polyvinylpyrrolidone and maltodextrin; and the gel formation aid is at least one member selected from the group consisting of water, sorbitol, glucose and glycerol.
4. A process according to claim 1, 2 or 3, wherein the warm formulation material is brought into a heated high pressure hose with the aid of a pump projecting into the heating tank and with regulated pressure and bypass control.
5. A process according to claim 4, wherein the heated high pressure hose is connected to a heated dosing head which is equipped with a spring-mounted ball valve and a nozzle.
6. A process according to claim 1, 2 or 3, wherein an adhesion-reducing releasing agent is placed on the inner surface of the cavity or blister.
7. A process according to claim 1, 2 or 3, wherein the film for forming the cavity has an unsealed zone from which one film project over the other by a few millimetres.
8. A process according to claim 6, wherein the formulation material and the releasing agent have opposite affinities.
9. A process according to claim 6, wherein in the case of a lipophilic or hydrophobic formulation material, water is atomized into the cavity or blister prior to the introduction of said formulation material.
10. A process according to claim 6, wherein in the case of a hydrophile formulation material, the inner surface of the cavity or blister is coated with a hydrophobic oil.
11. A process according to claim 1, 2 or 3, wherein the cavity or blister is formed of a thermoplastic material, thermo-plastic-coated aluminium or plastic-lined paper.
12. A process according to claim 6, wherein prior to removal of the cavity or blister, the releasing agent is applied to one side of a film to be shaped, said side subsequently constituting the inside of the cavity or blister.
13. A process according to claim 1, 2 or 3, wherein an agent favourably influencing the application and/or acceptance of the finished formulation material is applied to the inner surface of the cavity or blister.
14. A process according to claim 13, wherein the agent is a dye, flavour, sweetener, preservative or lubricant.
15. A process according to claim 1, 2 or 3, wherein the formulation material having a controllable sustained release action, the formulation material having a gastric juice resistance or the formulation material for buccal or sublingual application is applied to a substrate or placed in the cavity or blister.
16. A process according to claim 1, 2 or 3, wherein a chewing or sucking article is produced from the formulation material.
17. A process according to claim 1, 2 or 3, wherein the cavity or blister is successively filled with different formulation materials.
18. A process according to claim 17, wherein one coating contains the initial dose and the other coating the retard form.
19. A process according to claim 1, 2 or 3, wherein (a) the formulation material comprises at least one active substance selected from the group consisting of medicaments and dietetics.
20. A process according to claim 19, wherein, the active substance is a medicament; and the formulation material is processed at a temperature of 45 to 85°C at a pressure of 10 to 95 bar.
21. A process according to claim 20, wherein the formulation material is processed at a pressure of 35 to 55 bar.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3545090A DE3545090C1 (en) | 1985-12-19 | 1985-12-19 | Process for the production of individually dosed dosage forms |
| DEP3545090.8-32 | 1985-12-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1289074C true CA1289074C (en) | 1991-09-17 |
Family
ID=6288946
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000525681A Expired - Lifetime CA1289074C (en) | 1985-12-19 | 1986-12-18 | Process for producing individually dosed administration forms |
Country Status (9)
| Country | Link |
|---|---|
| EP (2) | EP0250578B1 (en) |
| JP (1) | JPH0778018B2 (en) |
| AU (1) | AU577213B2 (en) |
| CA (1) | CA1289074C (en) |
| DE (2) | DE3545090C1 (en) |
| DK (1) | DK165728C (en) |
| ES (1) | ES2021274B3 (en) |
| GR (1) | GR3002266T3 (en) |
| WO (1) | WO1987003805A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015131995A1 (en) * | 2014-03-03 | 2015-09-11 | Raisio Nutrition Ltd | Serum cholesterol lowering edible product |
| US10695313B2 (en) | 2013-07-05 | 2020-06-30 | Raisio Nutrition Ltd | Edible composition suitable for lowering serum cholesterol |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3914170C1 (en) * | 1989-04-28 | 1990-11-22 | Capsoid Pharma Gmbh, 7128 Lauffen, De | Pastille prepn. contg. vitamin(s) etc. - by dosing concave mould with liq. sol or gel mixt. contg. active ingredient, gelatin and water |
| GB9101502D0 (en) * | 1991-01-23 | 1991-03-06 | Controlled Therapeutics Sct | Controlled release compositions |
| JPH06190020A (en) * | 1992-12-25 | 1994-07-12 | Nippon Chemiphar Co Ltd | Packaged medical supply |
| FR2709420B1 (en) * | 1993-09-01 | 1995-11-17 | Sogeval | Veterinary tablet especially intended for cats. |
| DE4415999A1 (en) * | 1994-05-06 | 1995-11-09 | Bolder Arzneimittel Gmbh | Gastric acid-binding chewing pastilles |
| EP0916333A3 (en) * | 1997-11-14 | 1999-07-07 | Cetoni Umweltechnologie-entwicklungsgesellschaft mbH | Tablet and/or package for medical applications and/or for health care |
| EP2755639A2 (en) * | 2011-05-30 | 2014-07-23 | 2Lution GmbH | Solid solutions of polyphenols |
| DE102012221900A1 (en) | 2012-11-29 | 2014-06-05 | 2LUTION GmbH | Solid solution of caffeine and its derivative in a formulation material, useful as a dietary supplement, food or beverage or as a cosmetic agent, comprise a carrier material and solvent comprising glycerol and propylene glycol |
| WO2023025437A1 (en) * | 2021-08-25 | 2023-03-02 | Guido Knobel | Device for preparing a pharmaceutical, a food supplement or a cosmetic |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE7411652U (en) * | 1974-07-04 | Berthold + Sutter | Device for preparing and preparing a packing compound | |
| CH284791A (en) * | 1949-09-27 | 1952-08-15 | Toms Lab As | Machine for the injection molding of figures from plastic mass. |
| GB1388786A (en) * | 1972-04-03 | 1975-03-26 | Scherer Corp R P | Integral solid gel-lattice dosage form of high-moisture content |
| SE414386B (en) * | 1976-03-10 | 1980-07-28 | Aco Laekemedel Ab | VIEW TO PREPARE AND AT THE SAME PACKAGE PHARMACEUTICAL DOSAGE UNITS |
| FR2530421B1 (en) * | 1982-11-17 | 1985-09-27 | Lami Lutti | PROCESS FOR PRODUCING MOLDED GUM CONFECTIONERY AND PRODUCT THUS OBTAINED |
-
1985
- 1985-12-19 DE DE3545090A patent/DE3545090C1/en not_active Expired
-
1986
- 1986-12-12 JP JP62500777A patent/JPH0778018B2/en not_active Expired - Lifetime
- 1986-12-12 AU AU68416/87A patent/AU577213B2/en not_active Ceased
- 1986-12-12 WO PCT/EP1986/000740 patent/WO1987003805A1/en active IP Right Grant
- 1986-12-12 EP EP87900718A patent/EP0250578B1/en not_active Expired - Lifetime
- 1986-12-12 DE DE8787900718T patent/DE3678719D1/en not_active Expired - Lifetime
- 1986-12-18 EP EP86117669A patent/EP0227050B1/en not_active Expired - Lifetime
- 1986-12-18 ES ES86117669T patent/ES2021274B3/en not_active Expired - Lifetime
- 1986-12-18 CA CA000525681A patent/CA1289074C/en not_active Expired - Lifetime
-
1987
- 1987-07-29 DK DK396787A patent/DK165728C/en not_active IP Right Cessation
-
1991
- 1991-07-05 GR GR91400958T patent/GR3002266T3/en not_active IP Right Cessation
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10695313B2 (en) | 2013-07-05 | 2020-06-30 | Raisio Nutrition Ltd | Edible composition suitable for lowering serum cholesterol |
| US11771674B2 (en) | 2013-07-05 | 2023-10-03 | Raisio Nutrition Ltd | Edible composition suitable for lowering serum cholesterol |
| WO2015131995A1 (en) * | 2014-03-03 | 2015-09-11 | Raisio Nutrition Ltd | Serum cholesterol lowering edible product |
| US10532060B2 (en) | 2014-03-03 | 2020-01-14 | Raisio Nutrition Ltd. | Serum cholesterol lowering edible product |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0778018B2 (en) | 1995-08-23 |
| DE3678719D1 (en) | 1991-05-16 |
| GR3002266T3 (en) | 1992-12-30 |
| ES2021274B3 (en) | 1991-11-01 |
| WO1987003805A1 (en) | 1987-07-02 |
| EP0250578B1 (en) | 1991-04-10 |
| DK396787A (en) | 1987-07-29 |
| DK396787D0 (en) | 1987-07-29 |
| EP0250578A1 (en) | 1988-01-07 |
| AU6841687A (en) | 1987-07-15 |
| DE3545090C1 (en) | 1987-06-25 |
| DK165728C (en) | 1993-06-07 |
| AU577213B2 (en) | 1988-09-15 |
| EP0227050A1 (en) | 1987-07-01 |
| JPS63502430A (en) | 1988-09-14 |
| DK165728B (en) | 1993-01-11 |
| EP0227050B1 (en) | 1991-04-10 |
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| Date | Code | Title | Description |
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| MKLA | Lapsed |