AU3151400A - Method for producing film-type dosage forms - Google Patents

Description

Process for the production of sheet-like administration forms The present invention relates to sheet-like administration forms for application as cosmetic, pharmaceutical or food technological products. Flat-shaped administration forms for use in the oral region and on the mucous membranes of the mouth are well-known. Thus, US 3 444 858 (Russell, 1969) already describes me dicament strips based on a gelatine-like material. In EP 0 216 762 a water-soluble film of starch, gelatine, glycerine or sorbite is disclosed which is coated employing a roll-coating method. The document shortly mentions in this context that such dosage forms can also be produced for chemical reagents, flavours and the like. A formulation that is in principal suitable for making sheet-like systems is disclosed in EP 0 460 588. Here, the composition of 20 to 60 percent by weight of film former, 2 to 40% gelatinizing agent, 0.1 t 35 percent by weight of active substance (here: flavouring agent) and a maximum of 40 percent by weight of an inert filler is regarded as af fording particular advantages. DE 36 30 603 sees particular advantages in designing the flat-shaped dosage form on a carrier material (release film) so as to peelable in doses. US 4 128 445 and 4 197 289 (Sturzenegger, 1978) address possible technical solutions in connection with the loading with active substances.

2 For drug-containing sheet-like systems a two-layer struc ture of a water-swellable layer and a water-insoluble bar rier film is also regarded as advantageous (US 5 047 244). In the manufacture of such films, some hydrophile film formers, especially pullulan and other glucans, but also cellulose derivatives, exhibit insufficient wetting on com mon coating media. This may result in premature or diffi cult substrate detachment as well as a resultant uneven film thickness. As a remedy, US 4 562 020 recommends the use of a substrate circulating in the process as a loop, said substrate being based on nonpolar heat-stable polymers and, during the process, being continuously subjected to a superficial corona treatment, thus being constantly pro vided with a new polar surface that has a sufficiently safe wetting capability. The drying temperatures are between 40 and 110*C; temperatures mentioned in the Examples are 60 and 85 0 C. The aroma films produced on the pure film substrates have proved disadvantageous because of their being smooth on both sides. Such products have only limited suitability for the further processing and use in stacks formed by film cutting. Such stacks of film pieces or punched film pieces, as are frequently offered to the consumer in suitable dos age dispensers, tend to stick to each other, which makes it much more difficult to safely remove the pieces. As such film-shaped administration forms, due to their small weight per unit area (typically approx. 10 to 80 g/m 2 ) tend to be come statically charged, and since, at the same time, their surfaces, to facilitate later removal, are designed so as to be slidable on each other, this aspect is disturbing not only in use but also in the process technology. A third demand that should be met by the process is that loss of flavour due to heat be prevented while affording 3 maximum process rates. The prior art reveals no information pointing towards a solution to this demand. From these requirements, which have as yet remained un solved in the prior art, results the object of the present invention of providing processes for making sheet-like ac tive substance carriers which enable a precise and repro ducible coating quality, prevent the mutual adhesion of the finally produced pieces of film or sheet in the stack, and can be obtained, while avoiding contamination and excessive thermal load, at high production rates. This object is achieved according to the present invention in that immediately subsequent to the coating of the solu tion of hydrophile polymers with added active substances and further auxiliary substances, a stream of moderately warm air (30 - 50 0 C) is passed over the material, where after the temperature is raised slightly (35 - 80 0 C), fi nally followed by a reconditioning phase at 25 - 500C. The process rate is advantageously regulated such that a rela tive substrate humidity (equivalent humidity or equivalent air humidity) of 50 - 75% relative humidity, preferably 60 - 68% relative humidity, is maintained in all cases. By using rough-surface substrates, preferably thermoplasts of polypropylene, polyethylene, polyethylene terephthalate, polycarbonate, and laminates of these polymers, with poly ethylene-coated paper being particularly preferred, it is effectively prevented that the later-produced single film pieces stick to each other in a stack. The process according to the invention is applicable to any form of flat-shaped products - for example, for use as a food stuff, medicament or a cosmetic - which can be pro duced in a coating process from a mass which has been flu idized by solvents, especially water, and contains solid, 4 hydrophile base substances and optionally further compo nents. These hydrophile base substances may be polymers such as starch and its derivatives, agar-agar, gelatine, cellulose and cellulose derivatives, alginic acid, galactogluco mannan, carrageen, other vegetable gums permitted for the respective field of application, pullulan and other glu cans, dextrane, and polyvinylpyrrolidone, polyvinyl alcohol or polyacrylic acid homopolymers and copolymers. The poly vinyl alcohol used is advantageously a partially hydrolised form wherein between 1 and 20%, especially preferred: ap proximately 12%, of the hydroxyl groups are replaced by acetyl groups. The process according to the invention is effective in par ticular with problematic masses containing high portions of pullulan, carrageen or cellulose esters. Hydrophile additives of small molecular weight may also be employed, as structure-forming agents; these mostly serve to achieve application-specific objects. Possible additives are, inter alia, sugar, sugar alcohols, sugar substitutes, organic acids, polyethylene glycol. Solid substances which due to their poor solubility do not form a molecular-disperse mixture or solution in the base material may also be contained. Suitable substances are, for example, carbonates, phosphates, silicates, or sulfates of the alkali earth metals, zinc oxide, titanium oxide or other colour pigments, talcum, lactose, cyclodextrins or starch and starch derivatives, as far as they form their own, solid, disperse phase in the final product. The above list is exemplary only and can be completed by substances of the same function known to those skilled in the art.

5 Active components may, for example, be medicinal or cos metic active agents, dietary additives to foods, colourants or diagnostics. In particular, the process according to the invention can be employed with flavouring agents which are otherwise difficult to process because of their volatility. The flavours which may be used with this invention are mainly essential oils (volatile, water-insoluble distil lates of fragrant components of plants) and other volatile, fragrant substances having a limited miscibility with wa ter. Examples therefor are phenyl ethanol as a component of rose fragrance aromatics, menthol, eucalyptol (cineole), camphene and pinene in peppermint-like fresh flavourings, appetite inducing flavourings (spicing aromatics) such as, for example, n-butylphthalide or cineole, but also flavours having medicinal applications, such as eucalyptus oil, thyme oil, methyl salicylate, terpentine oil and camomile oil. A very broad field is taken up by essences and aromatics which are being used as additives in foods, and in prefab ricated food additives. Examples for these are the so called fruit ethers, but also other aromatics such as ethyl vanillin, 6-methylcoumarin, citronellol or n-butyl acetate. Additives of surface-active substances can improve the uni formity of the distribution of the droplets of aromatics. In special cases it may prove to be of advantage to apply one or more further layers of equal or different composi tion, in order to obtain special surface or tensile proper ties, for example. The mass is prepared, for example, by strewing-in, knead ing-in or slowly digesting the solid components in the sol vent (typically water, but also, e.g., ethanol, acetone and other compatible, physiologically acceptable solvents and mixtures thereof are employed). To this phase is added, 6 while stirring slowly, the pre-weighed amount of flavouring agent and other liquid, lipophile additives, as far as pro vided by the recipe. In the interest of the object of the invention, it has turned out to be of great advantage with respect to a uni form constitution to homogenize the mass, prior to coating, on a high-speed homogenizer. In the process according to the invention, the mass is coated on a substrate using a spread-coating, knife-coating or extrusion method, and is dried in a drying canal con sisting of at least three independently temperature controlled zones. The substrate may in principle consist of substrates known to those skilled in the art and widely used, such as, for instance, polyethylene terephthalate, polyethylene, poly propylene, polycarbonate, polyurethane. Also used are lami nates of these substances with other polymers, paper, fi breglass, and other structure-forming materials for in creasing tensile strength. To regulate surface adhesion it may be useful to take measures such as siliconization, fluorination, acid treatment or corona treatment, but these require clarification of their physiological tolerance for the relevant purpose of application in each individual case. Special advantages are achieved according to the invention if the surface facing towards the coating mass does not have a smooth contour, but a contoured, dulled, and in any case rough-surface contour. The peak-to-valley height can be in the range of 0.1 pm to about 10 pm, preferably be tween 0.5 and 3 pm. Of advantage are rounded protrusions in the microstructure, which further reduce sliding friction. The object of the present invention is regularly achieved where the drying takes place at a process temperature which 7 rises initially and is then, in the last zone at the lat est, reduced by 10 *C. Advantageously, the process rate is to be adjusted such that a product having an equivalent humidity of 50 - 75% relative humidity, preferably 60 - 68% relative humidity, is obtained. Under these process conditions the products obtained proved surface-stable, flexible and break-resistant as well as largely tear-resistant. The resultant surfaces exhibit vir tually no "cold flow" and are thus basically dimensionally stable. The film can be removed from the support without perceptible elongation occurring, and can be further proc essed separately. The equivalent air humidity is determined as follows: A freshly prepared product strip of about 0.1 m 2 in area is immediately and quickly folded, using rubber gloves, and placed in a wide-neck glass vessel, the cover of which is provided with a through-bore such that the measuring head of a hygrometer is introduced therein. After about a min ute, depending on the construction of the device, the meas ured value can be read. The further processing takes place, after longitudinal sec tion, in punching devices or simply by transverse section. The sheet-like products produced preferably have a thick ness of between 20 and 300 pm; their size may advanta geously range from 0.5 to 12 cm 2 . Subsequent packaging may take place singly or in a stack, for example in sealed pouches or dosage dispensers.

Claims (6)

1. Process for the production of sheet-like administra tion forms by way of coating and drying a solvent-contain ing, spreadable mass on a substrate, characterized in that the drying is performed up to a relative substrate humidity (equivalent air humidity) of 50 - 75% relative humidity, preferably 60 - 68% relative humidity.

2. Process according to claim 1, characterized in that the sheet-like product contains flavours.

3. Process according to claim 1 or 2, characterized in that the sheet-like product contains pullulan as main com ponent.

4. Process according to one or more of the preceding claims, characterized in that the drying of the laminate takes place in the first temporal third of the drying stage at between 30 and 50*C, in the second third at between 35 and 80 0 C, and in the last third at between 25 and 50 0 C.

5. Process according to one or more of the preceding claims, characterized in that the drying of the sheet-like product takes place on a material having a rough surface.

6. Process according to Claim 5, characterized in that a polyethylene-coated paper is used as the material having a rough surface.