|Title of Invention||
"MULTILAYER PREPARATION FOR A CONTROLLED, PULSED RESEASE OF ACTIVE SUBSTANCES"
|Abstract||A multilayer preparation for controlled, pulsatile delivery of active ingredients is characterized in that the preparation has at least four layers, of which at least two nonadjacent layers contain any active ingredient A.|
|Full Text||Multilayer preparation for controlled, pulsatile delivery of active ingredients
The invention relates to a multilayer preparation for controlled, pulsatile delivery of active ingredients.
With most dosage forms for active ingredients, especially pharmaceutical forms, it is desired for the time course of active ingredient release to be as uniform as possible. However, there are use situations in which such a uniform active ingredient release is less expedient, so that ways must be sought to make it possible for there to be periodic, pulsatile release.
The use of dosage forms with pulsatile release characteristics is a great advantage for example in nicotine replacement for achieving abstinence from smoking, and possibly in replacement therapies for other- addictions.
Nicotine consumption, especially by means of cigarettes, is increasingly in the forefront of public interest, not only because of its harmful effects on the health of the smoker himself but also because of the problems of passive smoking and the nuisance or harm to the health of other people which is associated therewith. For this reason there are on the market active ingredients and dosage forms which aims at gradually achieving abstinence of the smoker from his daily nicotine requirement. With other products the main aim is not the abstinence-achieving effect; on the contrary they are intended only to provide the required amount of nicotine in a form which can be consumed without the upsetting and health-harming secondary effects of smoking. Known representatives of this group are, for example, nicotine patches and nicotine chewing gum.
For nicotine replacement therapy to be successful, it is important not to ignore the pleasure aspect. An important
part in this appears to be played by pulsatile administration of nicotine, as takes place when a cigarette is smoked. It is evident that what is crucial for pleasure is not a constant, continuous intake of nicotine but a discontinuous, intermittent administration, possibly of different doses, taking place at intervals. The smoker brings this effect about by time intervals of appropriate length between the individual puffs, and by duration thereof.
By contrast, dosage forms hitherto disclosed for nicotine replacement provides the active ingredient nicotine not in a sequence of pulsatile active ingredient peaks but, on the contrary, as a constant stream of active ingredient. Although this attains a substantially constant level of active ingredient, insufficient attention is paid to the pleasure aspect. It is to be presumed that dosage forms which bring out pulsatile nicotine release will have a more successful replacement and abstinence-achieving effect. This assumption is prompted by investigations which showed that pulsatile administration of a nicotine-containing nasal spray in addition to a constant intake of nicotine through a skin patch brought about a significant improvement in achieving abstinence from nicotine (Medical Tribune, 16 Apr 1999, MAbschied vom blauen Dunst"; and: Blondal, T., Stapleton, J., British Medical Journal, Vol. 318, No. 7179 (1999), p. 285-289).
US 5 783 207 describes a nicotine-containing dummy which is is composed of two or more nicotine-containing layers. These layers may have different dissolution rates and, in particular, the outermost layer may be designed as rapidly releasing layer. However, because of the presence of nicotine in all the layers, the desirable pulsatile release does not occur.
Another nicotine-containing dosage form is disclosed in
V US 5 S25 351. This consists of two nicotine-containing
layers, nicotine release being rapid from the first and slow from the second. It is not possible to achieve repeated, pulsatile release in this case either.
Besides these nicotine-containing dosage forms, also known from the prior art are other dosage forms which have a multilayer structure and which are suitable in principle for gradual delivery of active ingredients.
EP 0 348 683 describes a tablet consisting of three layers. This tablet contains in two layers two active ingredients which are mutually incompatible. Between these two layers there is a third layer which is pharmacologically inactive and serves merely as a separating layer. In this case, the layer structure serves merely for special separation of two incompatible active ingredients.
US 5 560 169 likewise discloses a three-layer tablet in which there is a barrier layer between two active ingredient-containing layers. The tablet is entirely - apart from a small area - covered by an impermeable polymer layer. The layer structure is moreover not concentric.
One variant of the above dosage form is described in US 4 865 849 or EP 0 274 734. In this case, the barrier layer and the second active ingredient-containing layer are coated with an impermeable, water-insoluble covering which is, however, soluble in an alkaline medium. This makes these layers physiologically accessible only after destruction or dissolution of the covering. It is also possible for more than two layers to be present inside the covering. As with the multilayer system described in US 5 650 169, once again the structure is not concentric.
A multilayer dosage form with special properties is disclosed in US 5 575 819. This comprises pollen grains which are filled with active ingredient and then provided with a multilayer coating, it being possible for the surrounding layers likewise to contain active ingredients.
For administration, these pollen grains are introduced into capsules, tablets etc. They are intended in particular for the veterinary sector.
US 5 Oil 692 describes a multilayer dosage form in which only every second layer contains an active ingredient. The layers are covered on their edge surface by a water-insoluble layer; the latter also covers one side of the layers.
Periodic, pulsatile release characteristics as required, for example, for the purpose of achieving abstinence from nicotine or other comparable use situations is not or is only approximately achieved with the multilayer dosage forms mentioned.
It was therefore the object of the present invention to design a dosage form for active ingredients which makes controlled, pulsatile release of active ingredients possible. The object was in particular to design a. nicotine-containing preparation which, because of its pulsatile release characteristics, is particularly suitable for achieving abstinence from nicotine.
The object is achieved, for example, by a multilayer preparation according to the main claim, which has at least four layers, of which at least two nonadjacent layers contain any active ingredient A. It is possible in this way, depending on the number and configuration of the layers, for there to be pulsatile release of active ingredient A throughout a desired period.
It is possible and preferable for the layers, or at least some of these layers, which do not contain the active ingredient A, to have a configuration such that they are dissolved or eroded more slowly than are the layers which contain the active ingredient A. This can be achieved by different layer thicknesses as well as by a different composition of the individual layers, or by both. The
dissolution or erosion of the layers not containing the active ingredient A can take a time which is 1.01 to 100,000 times, preferably 1.2 to 1000 times, particularly preferably twice to 100 times the time required for dissolution or erosion of the layer containing active ingredient A. The rate of dissolution or erosion of individual layers may be, depending on the embodiment of the invention, between 1 second and up to 1 month. Dissolution rates are preferably in the range from 1 second to 1 day, particularly preferably in the range from 1 second to 10 minutes.
A further possibility is for the layers containing the active ingredient A, or at least some of these layers, to be designed as rapidly disintegrating, eroding or soluble layers, which leads to a correspondingly increased rate of active ingredient release ("quick release").
It is possible by a suitable choice of the solubility or erosion or disintegration properties of the layers to control the release characteristics, specifically the length of the interval between the active ingredient peaks and the pulse shape.
In a preferred embodiment, the preparations according to the invention have a concentric, either centrosymmetric structure, for example spherical or approximately spherical (Figure 1), or an axisymmetric structure (Figs. 2 and 3), preferably prolate ellipsoidal or cylindrical. The layers are in these cases arranged concentrically like the layers of an onion around a centrally located core which represents the innermost layer. The latter can, depending on requirements, likewise contain the active ingredient A or other active ingredients, or be free thereof.
In another embodiment, the individual layers are designed as sheet-like laminate so that no concentric structure is present. In this case too there is between two layers containing the active ingredient A and at least one other layer which does not contain this active ingredient.
However, this does not preclude another active ingredient or auxiliaries being present in any desired layer. Fig. 4 shows such an embodiment in a sectional view (Fig. 4a) and plan view (Fig. 4b), it being possible for the shape of the laminate to have round or angular structural features. It is possible in this case for at least one of the layers to be a contact adhesive which joins the individual layers together. In order to prevent active ingredient escaping from the edge surfaces of the geometrical body in the sheet-like laminate depicted in the sectional view in Fig. 4a, these surfaces can be provided with at least one water-impermeable layer (4).
Both with the sheet-like and with the concentric structure, particular embodiments are also provided in which the multilayer preparation is configured in the form of a dummy. Otherwise, the preparations according to the invention can be produced in the form of uncoated tablets, film-coated tablets, suckable tablets or sugar-coated tablets.
A particularly preferred embodiment is one where active ingredient A is represented by nicotine. In this case, the multilayer tablet is designed as suckable tablet, with each nicotine-containing layer with rapid release characteristics being followed by a nicotine-free layer which dissolves only slowly. On sucking, this leads to initial release of an active ingredient peak, and it is then necessary to dissolve the subsequent nicotine-free layer by sucking until the next nicotine-containing layer is accessible and another active ingredient peak can be delivered. It is thus possible to simulate by a plurality of such layers the nicotine dosage scheme of a cigarette. A structure of this type complies in the best possible way with the requirement for pulsatile nicotine release at intervals to attain an optimal abstinence-achieving effect. The invention also, of course, embraces embodiments of the type just described in which nicotikie is replaced by another active ingredient.
the layers depends inter alia, as described above, on the desired erosion or dissolution rate. There is provision of embodiments in which all the layers have approximately the same thickness, as well as those in which at least one layer has a thickness differing from the other layers.
In other preferred embodiments, the layers may, irrespective of whether they contain active ingredient A or not, contain one or more other types of active ingredients. It is possible in particular for the layers which contain no active ingredient A to contain at least one other active ingredient of a different type. In this case too, it is possible for there to be an alternating sequence, but other arrangements can also be used. It is possible and preferable for the layers which contain an active ingredient different from A, or several such active ingredients, also to be designed as rapidly releasing layers.
The preparation may also contain two or more active ingredients which, after oral intake, are released after particular times have elapsed. Thus, a multilayer preparation which, for example, contains three active ingredients each in a separate active ingredient-containing layer may release the first active ingredient shortly after intake (for example in the morning), the second active ingredient after a particular time has elapsed (for example at midday) and the third active ingredient after a further time has elapsed (for example in the -evening).
The active ingredient concentration may be at the same level in the individual layers, but in some cases it may be necessary for the layers, or at least some of the layers, to have different active ingredient concentrations. A problem which emerges with multilayer preparations with a concentric structure is that the decrease in the radii towards the centre leads to the active ingredient content per layer continuously decreasing. In order to compensate for this, it may be" appropriate, for example, to increase the active
ingredient concentrations appropriately in the layers, or to vary the thickness of the layers or their solubility, or to add suitable additives such as, for example, enhancers. Differences in concentration of the active ingredient(s) in the individual layers may not only serve to compensate for the regions of differing active ingredient content due to the geometric design, but also to modulate the active ingredient release in a desired manner.
Besides nicotine, another active ingredient A which is particularly preferably used is aspirin. In addition, active ingredients which can be added either as active ingredient A or as additional active ingredients to the layers of the preparation and which are particularly suitable are the following:
Active ingredients from the groups of parasympatholytics (for example scopolamine, atropine, benactyzine), of the cholinergics (for example physostigmine, nicotine), of the neuroleptics (for example chlorpromazine, haloperidol), of the monoamine oxidase inhibitors (for example tranylcypromine, selegiline), of the sympathomimetics and antisympathotonics (for example propranolol, timolol, bupranolol, clonidine, dihydroergotamine, naphazoline), of the anxiolytics (for example diazepam, triazolam), of the local anaesthetics (for example lidocaine), of the central analgesics (for example fentanyl, sufentanil), of the antirheumatics (for example indomethacin, piroxicam, lornoxicam), of the coronary therapeutics (for example glycerol trinitrate, isosorbide dinitrate), of the oestrogens, gestagens and androgens, of the antihistaminas (for example dphenhydramine, clemastine, terfenadine), of the prostaglandin derivatives, of the vitamins (for example vitamin E, cholecalciferol) or of the cytostatics and of the cardiac glycosides such as, for example, digitoxin and digoxin.
The individual layers may, irrespective of whether they contain active ingredients or not, additionally contain flavourings, colourings, disintegration-promoting additives, absorption promoters or sweeteners. It is moreover possible for all layers, including where appropriate of the core, to have the same additives. However, the invention also embraces embodiments in which the individual layers, and where appropriate the core, differ with regard to the content of additives.
A particularly preferred variant of the invention is one in which each second layer contains the active ingredient A, and the layer located in between in each case is free of active ingredient A, so that the result is an alternating sequence of active ingredient-containing and active ingredient-free layers. The invention additionally includes embodiments in which there are arranged between the layers containing the active ingredient A two or more layers which do not contain this active ingredient. It is moreover possible to have an alternating sequence (Fig. 5), but other types of arrangements (Fig. 6) may also be advantageous. The outermost layer of the preparation may likewise contain active ingredient A and/or at least one other active ingredient, but it may also, if advantageous, be free of active ingredients.
It is possible and preferable for the multilayer preparation to have up to 60 layers containing the active ingredient A, a structure composed of 5 to 30 of such layers being more preferred, and a structure composed of 6 to 15 of such layers being particularly preferred. The total number of layers is according to the main claim at least four, but preferably at least five, and particularly preferred embodiments have at least 10 layers.
The thickness of the individual layers is between 1 and 5000 µm, preferably between 10 and 2000 µm, particularly preferably between 20 and 500 µm. The selected thickness of
Particularly preferred active ingredients have central activity and are prone on continuous release to lead to a habituation effect on the receptors. Concerning pharmacokinetics, they rapidly enter the blood, that is to say they very quickly reach the relevant receptor. In addition, they are rapidly degraded, that is to say they are rapidly metabolized, for example in the region of seconds or minutes.
The multilayer preparations according to the invention are preferably used as uncoated tablets or suckable tablets for oral administration. Depending on the active ingredients employed and on the particular area of use, however, it is possible for other embodiments to be more advantageous, for example for rectal or vaginal administration, or in the form of implants. In addition, the preparations according to the invention are also suitable for administering active ingredients in veterinary medicine.
It is possible in principle for the multilayer preparations according to the invention to be employed advantageously wherever it is important for there to be pulsatile release, taking place at intervals, of an active ingredient or other substance to the surrounding medium. This includes applications in the agricultural, horticultural, industrial and domestic sectors (for example tablets for dishwashing compositions or detergents).
The basic material of the active ingredient-containing as well as active ingredient-free layers may contain the following ingredients: polymers such as polyisobutylene, esters of polyvinyl alcohol, polyacrylic acid, polymethacrylic acid and poly(methyl methacrylate) and derivatives thereof, natural rubber, styrene, isoprene, and styrene, butadiene polymers or silicone polymers, resin constituents such as saturated or unsaturated hydrocarbon resins, derivatives of abietyl alcohol and of p-pinene; also plasticizers such as phthalic esters, triglycerides and
fatty acids, and a number of other substances known to the skilled person.
It is possible for all the layers or individual layers, for example only the outermost layer or layers, to be designed to be resistant to gastric fluid. This can be achieved by using, for example, wax, sealing wax, ethylcellulose or other materials known to the skilled person. Preferred embodiments are those in which at least one layer is designed to be resistant to gastric fluid. This may be the outermost layer or at least one of the inner layers, appropriate for the intended use.
The layers of the dosage form according to the invention may, besides one or more active ingredients and a carrier substance as filler, also contain further auxiliaries as additions. These auxiliaries are classified according to their function as plasticizers, tackifiers, absorption promoters, stabilizers or flow regulators. Substances of these types, which must be physiologically acceptable, are known in principle to the skilled person.
The substances employed as carrier substance or fillers are those having the solubility, erosion or swelling properties appropriate for the requirements. Typical substances for this purpose are, for example, lactose, cellulose types, sugar alcohols such as, for example, mannitol and sorbitol, various starch types and alginates.
Examples of coating substance soluble in gastric fluid
employed are acrylic acid derivatives such as Eudragit L and Eudragit® S, polyvinyl alcohols,
hydroxypropylmethylcellulose acetate phthalate or cellulose acetate phthalate, and of substances soluble in the small
bowel are polyacrylic esters such as, for example, Eudragit E30D, polyacrylic acid derivatives, shellac or cellulose such as methyl- or ethylcellulose.
alternating sequence. The active ingredient-free layers (2) are shown pale and the active ingredient-containing layers (1) are shown dark, and a further layer (3) is shown black.
Figure 6 shows a section through a centrosyiranetric embodiment of the invention which has active ingredient-free layers and active ingredient-containing layers not in alternating sequence. The active ingredient-free layers (2) are shown pale, the active ingredient-containing layers (1) are shown dark, and a further layer (3) is shown black.
9. A preparation according to one or more of the preceding
claims, whose layer structure is characterized in that in an
alternating sequence in each case a layer containing the
active ingredient A is in contact with an adjacent layer in
each case, which does not contain this active ingredient or
contains it in considerably smaller amounts.
10. A preparation according to one or more of the preceding
claims, characterized in that at least two layers which do
not contain the active ingredient A are present between the
layers containing active ingredient A.
11. A preparation according to one or more of the preceding
claims, characterized in that one or more layers contain an
active ingredient different from active ingredient A, or
several such active ingredients, singly or in combination.
12. A preparation according to one or more of the preceding
claims, characterized in that the layers containing no
active ingredient A are free of active ingredient.
13. A preparation according to one or more of the preceding
claims, characterized in that the active ingredient
concentrations are at different levels in at least some of
the active ingredient-containing layers.
14. A preparation according to one or more of the preceding
claims, characterized in that at least one layer has a
thickness differing from the other layers.
15. A preparation according to one or more of the preceding
claims, characterized in that it is in the form of a dummy,
of a suckable tablet, of a film-coated tablet, of an
uncoated tablet or of sugar-coated tablets.
16. A preparation according to one or more of the preceding
claims, characterized in that the individual layers
V additionally contain, irrespective of whether they contain
The following processes can advantageously be employed for producing the dosage form according to the invention: spray coating, the compression or sintering processes known to the skilled person, and the lamination of individual layers to give a laminate, or multiple coating by means of the hot melt process or other processes known to the skilled person for multiple coating. The process according to the invention shows how preparations according to the invention with a concentric or sheet-like structure can be produced in a relatively simple way by a combination of suitable process steps.
Figure 1 shows a section through a centrosymmetric embodiment of the invention. In this case, the active ingredient-free layers (2) are shown pale, and the active ingredient-containing layers (1) are shown dark.
Figures 2 shows a section through an axisymmetric embodiment of the invention. In this case, the active ingredient-free layers (2) are shown pale, and the active ingredient-containing layers (1) are shown dark.
Figure 3 shows a section through an axisymmetric embodiment of the invention in which all the layers come into contact through their edge surface with the surrounding medium. The active ingredient-free layers (2) are shown pale and the active ingredient-containing layers (1) are shown dark.
Figure 4 shows a sheet-like laminate comprising an alternating number of layers containing the active ingredient A (1) and not containing the active ingredient A (2). Figure 4a shows the laminate in a side view (sectional view) with the optional water-impermeable layer (4) on the edge surfaces, and Figure 4b shows a plan view of embodiments with geometrically different designs.
Figure 5 shows a section through a centrosymmetric embodiment of the invention which contains active ingredient-free and active ingredient-containing layers in
1. A multilayer preparation for controlled, pulsatile delivery of active ingredients in the oral cavity, wherein the preparation has at least five layers which are disintegrating layers, credible layers or soluble layers, wherein in an alternating sequence in each case a layer containing any active ingredient A is located on an adjacent layer in each case, which adjacent layer does not contain this active ingredient or contains it in considerably smaller amounts, and wherein said layers are arranged concentrically around an inner core which forms the innermost layer of the preparation, and said adjacent layers not containg said active ingredient A are dissolved or eroded more slowly than said layers containing said active ingredient A, due to the different thickness and/or the different composition of said layers; and wherein said active ingredient(s) is/are selected from the group comprising parasympatholytics, cholinergics, neuroleptics, monoamine oxidase inhibitors, sympathomimetics and antisympathotonics, anxiolytics, central analgesics, antirheumatics, coronary therapeutics, oestrogens, gestagens and androgens, antihistamines, prostaglandin derivatives, vitamins, cytostatics and cardiac glycosides.
2. A preparation as claimed in claim 1, wherein at least the layers
containing the active ingredient A are designed as rapidly disintegrating,
eroding or soluble layers.
3. A preparation as claimed in claim 1 or 2, wherein the layers that are
arranged concentrically around said core-the innermost layer-result in
spherical or axisymmetrical, preferably prolate ellipsoidal or cylindrical
4. A preparation as claimed in any of claims 1 to 3 wherein the active
ingredient A is nicotine.
5. A preparation as claimed in one or more of the preceding claims, where at
least two layers which do not contain the active ingredient A are p[resent
between the layers containing active ingredient A.
6. A preparation as claimed in one or more of the preceding claims , wherein
one or more layers contain an active ingredient different from active
ingredient A, or several such active ingredients, singly or in combination.
7. A preparation as claimed in one or more of the preceding claims, wherein
the layers containing no active ingredient A are free of active ingredient.
8. A preparation as claimed in one or more of the preceding claims, wherein
the active ingredient concentrations are at different levels in at least some
of the active ingredient-containing layers.
9. A preparation as claimed in one or more of the preceding claims, wherein
at least one layer has a thickness differing from the other layers.
10. A preparation as claimed in one or more of the preceding claims,
wherein said preparation is in the form of a lollipop, of a suckable tablet,
of a film-coated tablet, of an uncoated tablet or of sugar-coated tablets.
11. A process for the production of preparations as claimed in claim 1,
wherein for producing said multilayer preparation having a concentric
structure, initially a core is shaped, the latter is transferred to a spray-
coating system and coated alternately with layers containing the active
ingredient A and with layers not containing the active ingredient A, and is
then packed singly or as ensemble.
|Indian Patent Application Number||IN/PCT/2002/00502/DEL|
|PG Journal Number||10/2008|
|Date of Filing||14-May-2002|
|Name of Patentee||LTS LOHMANN THERAPIE-SYSTEM AG|
|Applicant Address||LOHMANNSTRASSE 2, 56626 ANDERNACH GERMANY.|
|PCT International Classification Number||A61K 9/22|
|PCT International Application Number||PCT/EP00/10934|
|PCT International Filing date||2000-11-06|