KR100690518B1 - Multilayer preparation for a controlled, pulsed release of active substances - Google Patents

Abstract

The multi-layered medicament for controlled, pulsatile release of the active ingredient is characterized in that it has at least four layers, at least two non-adjacent layers containing any active substance A.

Multilayer Pharmaceutical, Pulsating Release

Description

MULTILAYER PREPARATION FOR A CONTROLLED, PULSED RELEASE OF ACTIVE SUBSTANCES}

The present invention relates to a multi-layered medicament for controlled delivery of pulsatile (ie pulsed) active ingredients.

Most dosage forms, particularly pharmaceutical forms, of the active ingredient are desired to release the active ingredient as uniformly as possible over time. However, there are situations of use in which release of such a uniform active ingredient is not suitable, and therefore, a method must be found to enable periodic, pulsatile release.

The use of dosage forms with pulsatile release properties is very useful, for example, as a nicotine replacement for achieving smoking cessation, and can be used in alternative therapies for other addictions.

In particular, nicotine consumption by cigarettes has attracted more and more public attention not only because of the adverse effects on smokers' own health, but also because of the problems of secondhand smoke and the health of others around them. For this reason there are commercially available active ingredients and dosage forms aimed at progressively achieving the withdrawal of the daily nicotine requirement of smokers. Other products are not intended to have the withdrawal effect; Rather, the aim is to provide the amount of nicotine in a form that can only be consumed without the secondary effects that are detrimental to the health of smoking. Known representative examples of these include nicotine patches and nicotine chewing gum.

To succeed in nicotine replacement therapy, it is important not to ignore the pleasure aspect. An important part here is the pulsatile administration of nicotine occurs when a cigarette is smoked. It is clear that what is important for pleasure is not constant and continuous nicotine intake, but discontinuous and periodic administration in different amounts at intervals. The smoker obtains this effect according to the appropriate time interval and duration of the funding minutes.

In contrast, conventional dosage forms known as nicotine replacements provide the active ingredient nicotine by a constant flow of the active ingredient rather than by a series of pulsatile active ingredient peaks. This is insufficient in terms of pleasure, even if a substantially constant level of active ingredient is obtained. Dosage forms that cause pulsatile nicotine release are thought to have more successful replacement and withdrawal effects. This premise is made possible by studies showing that administration of nicotine-containing nasal sprays significantly improves nicotine withdrawal in addition to the constant absorption of nicotine through skin patches (Medical Tribune, 16 Apr 1999, "Abschied 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 consisting of two or more nicotine containing layers. These layers differ in dissolution rate and are especially designed to release the outermost layer faster. However, since nicotine is present in all layers, the desired pulsatile release does not occur.

US Pat. No. 5,525,351 describes another nicotine containing dosage form. It consists of two nicotine containing layers, the nicotine release from the first layer is fast and the nicotine release from the second layer is slow. In this case too, it is impossible to achieve repeated, pulsatile release.

In addition to such nicotine containing dosage forms, other dosage forms are known which have a multilayer structure and which are basically suitable for the progressive release of the active ingredient.

EP O 348 683 describes a three-layer tablet. This tablet contains two active ingredients in combination with each other in two layers. A pharmacologically inactive third layer between these two layers simply serves as a separating layer. In this case, the layer structure serves to specially separate only two compounding contraindications.

US 5 560 169 likewise describes three layer tablets with a barrier layer between two active ingredient-containing layers. The tablet is almost entirely covered with a layer of impermeable polymer except for a small area. Furthermore the layer structure is not concentric.

US 4 865 849 or EP 0 274 734 describes one variant of this dosage form. In this case, the barrier layer and the second active ingredient-containing layer are covered with an impermeable, water-soluble sheath that is soluble in an impermeable, water-insoluble or alkaline medium. These layers are physiologically accessible only after eroding or dissolving the shell. Also two or more layers may be present inside the shell. As with the multilayer system described in US 5 650 169, the structure is not concentric.

US 5 575 819 describes multilayer dosage forms with special features. It consists of pollen grains coated with the active ingredient and then multi-layer coated, and the surrounding layers may also contain the active ingredient. For administration, these pots are placed in capsules, tablets and the like. They are specifically designed for the veterinary field.

US 5 011 692 describes multilayer dosage forms containing the active ingredient only in the second layer. The layers are covered with a layer whose edge surface is insoluble in water; The layer insoluble in this water also covers one side of the layers.

The periodic, pulsatile release properties required, for example, for nicotine withdrawal or other similar use situations, may or may not be attainable only with the multilayer dosage forms described above.

It is therefore an object of the present invention to design active ingredient dosage forms which enable controlled, pulsatile release of the active ingredient. In particular, it is an object of the present invention to design nicotine containing medicaments which are particularly suitable for achieving nicotine withdrawal due to its pulsatile release properties.

The object of the present invention is achieved by a multilayered medicament according to the claims, for example, having at least four layers, of which at least two nonadjacent layers contain any active ingredient A. According to this method, pulsatile release of active ingredient A is possible for a desired period, depending on the number and shape of the layers.

It is preferred that the layers not containing active ingredient A, or at least some of these layers, have a form that dissolves or corrodes more slowly than the layers containing active ingredient A. This can be achieved by different compositions of the individual layers as well as by different thicknesses or both. The time taken for dissolution or corrosion of the layers not containing the active ingredient A is 1.01 to 100,000 times, preferably 1.2 to 1,000 times, particularly more preferably the time required for dissolution or corrosion of the layer containing the active ingredient A. 2 to 100 times In accordance with an aspect of the present invention, the dissolution or corrosion rate of the individual layers is preferably 1 second to 1 month. The dissolution rate is preferably in the range of 1 second to 1 day, and particularly preferably in the range of 1 second to 10 minutes.

The layers containing the active ingredient A, or at least some of these layers, can be designed to decompose quickly, corrode or dissolve, thereby relatively increasing the release rate of the active ingredient (“fast release”).

By suitably selecting the solubility or corrosion or degradability of the layers it is possible to control the emission properties, in particular the duration of the interval between the active component peaks and the pulse form.

In a preferred embodiment, the medicament according to the invention has a concentric, for example spherical or nearly spherical, center symmetrical structure (FIG. 1) or axisymmetric structure (FIGS. 2 and 3), preferably a long ellipsoidal. Or cylindrical. In this case the layers are arranged concentrically like layers of onion around a centrally located core representing the innermost layer. If necessary, the innermost layer may or may not contain active ingredient A or another active ingredient.

In another aspect, the individual layers are designed in sheet-like laminates without concentric structures. In this case also there is at least one other layer which does not contain active ingredient A between the two layers containing active ingredient A. However, this does not exclude the presence of another active ingredient or adjuvant in any desired layer. 4 is a cross-sectional view (FIG. 4A) and a plan view (FIG. 4B) of the above aspect, and the shape of the laminate may be rounded or angled. In this case at least one of the layers may be a contact adhesive that bonds the individual layers together. In order to prevent the active ingredient from leaking out of the edge surface of the geometry in the sheet-like laminate shown in the cross-sectional view of FIG. 4A, at least one water can be provided on these surfaces 4.

Using both the sheet-like and concentric structures described above, certain embodiments are also provided in which the multi-layered medicaments are arranged in a dummy form. On the other hand, the medicaments of the present invention may be prepared in the form of uncoated tablets, film coated tablets, suckable tablets or sugar coated tablets.

In a particularly preferred embodiment, the active ingredient A is nicotine. In this case, the multilayer tablet is designed as an absorbent tablet in which each nicotine containing layer has fast release properties and then the nicotine free layers slowly dissolve. Upon sucking, this leads to the initial release of the active ingredient peak, which then allows the use of a nicotine containing layer to dissolve the subsequent nicotine free layer by inhalation until another active ingredient peak can be released. Needs to be. Thus, a plurality of the layers may be similar to the nicotine administration scheme of cigarettes. This type of structure is the most likely method for the need for periodic pulsatile nicotine release to achieve optimal withdrawal effects. The present invention also naturally encompasses embodiments of the type described above in which nicotine is replaced by another active ingredient.

Individual layers may further contain spices, colorants, degradation additives, absorption accelerators or sweeteners, whether or not they contain active ingredients. All layers may also contain the same additives as above, including when used as a core. On the other hand, the present invention also encompasses aspects in which the individual layers, when also using the core, differ in content of additives.

A particularly preferred variant of the invention is that each second layer contains the active ingredient A, and in each case there is no active ingredient A, so that the active ingredient containing layer and the no active ingredient are arranged alternately. It is. The invention also encompasses an embodiment in which two or more layers containing no active ingredient are arranged between the layers containing active ingredient A. They can also have alternating sequences (FIG. 5), but other arrangements are useful (FIG. 6). The outermost layer of the medicament likewise contains active ingredient A and / or at least one other active ingredient, but may not contain the active ingredient if necessary.

The multilayer medicament may preferably be up to 60 layers containing the active ingredient A, more preferably a structure consisting of 5 to 30 layers, particularly preferably a structure consisting of 6 to 15 layers. According to the claims of the present invention, the total number of layers is at least 4, preferably at least 5, with a particularly preferred aspect having at least 10 layers.

The thickness of the individual layers is in the range of 1 to 5,000 μm, preferably in the range of 10 to 2,000 μm, particularly preferably in the range of 20 to 500 μm. The selected thickness of the layers depends in particular on the desired corrosion or dissolution rate, as described above. In some embodiments, all layers have approximately the same thickness, as well as at least one layer having a thickness different from the other layers.

In another preferred embodiment, the layers may contain one or more other types of active ingredients, whether or not they contain active ingredient A. In particular, the layers which do not contain active ingredient A may contain at least one other active ingredient of a different type. In this case as well, alternate arrangements can be made, but other arrangements can be applied. The layer containing A and other active ingredients or several such active ingredients can be designed in layers which are preferably quickly released.

The drug may contain two or more active ingredients released after oral ingestion and after a specific time has elapsed. Thus, for example, a multi-layered drug each containing three active ingredients in a separate active ingredient-containing layer releases the first active ingredient immediately after ingestion (e.g., morning) and after a certain time has elapsed (e.g., The third active ingredient may be released after a longer period of time (e.g. in the evening) after the second active ingredient has been released.

The concentration of the active ingredient may be at the same level in the individual layers, but in some cases the layers, or at least some of the layers, need to vary the concentration of the active ingredient. The problem with concentric multi-layered drugs is that the radius decreases toward the center so that the content of active ingredient per layer continues to decrease. To compensate for this, for example, it is suitable to increase the concentration of the active ingredient in the layers as appropriate, change the thickness of the layers or their solubility, or add a suitable additive such as an enhancer. can do. The difference in the concentration of the active ingredient (s) in the individual layers makes it possible to control the release of the active ingredient in the desired manner, as well as to compensate for other sites in which the content of the active ingredient due to the geometrical design.

In addition to nicotine, another active ingredient A which is particularly preferably used is aspirin. In addition, particularly preferred active ingredients which can be added to the pharmaceutical layer as active ingredient A or as additional active ingredients are:

Parasympathetic blockers (e.g., scopolamine, atropine, benathizin), choline agonists (e.g., physostigmine, nicotine), neuroleptics (e.g., chlorpromazine, haloperidol), monoamine oxidase inhibitors (e.g. Eg, tranylcypromine, selegiline, sympathetic and parasympathetic agents (e.g. propranolol, timolol, bupranolol, clonidine, dihydroergotamine, napazoline), anxiolytics (e.g., Diazepam, triazolam), local anesthetics (e.g. lidocaine), central analgesics (e.g. fentanyl, sufentanil), antirheumatics (e.g. indomethacin, pyroxam, lornoxicam), coronary artery remedies (Eg, glycerol trinitrate, isosorbide dinitrate), estrogens, gestagens and androgens, antihistamines (eg dephenhydramine, clemastine, terpenadine), prostaglandin derivatives, vitamins ( Yes, vitamin E, cholecalcium Ferrol) or cell growth inhibitors and cardiac glycosides (e.g., digitoxins and digosines).

Particularly preferred active ingredients have a major activity and tend to release continuously, thus habitually affecting the receptor. With regard to the body's response to drugs, they quickly enter the blood, that is to say to the relevant receptors very quickly. In addition, they are rapidly degraded, that is to say metabolized rapidly, eg in the range of seconds or minutes.

The multi-layered medicament according to the present invention is preferably used as an uncoated tablet or an aspiration tablet for oral administration. However, depending on the active ingredient and the particular site of use applied, other embodiments are possible which are more useful, for example, for rectal or vaginal administration, or in implantable form. In addition, the medicament according to the invention is also suitable for administration of the active ingredient in veterinary medicine.

Basically, the multilayered drug according to the present invention can be usefully applied in any case where it is important to periodically release the active ingredient or other substance to the surrounding medium. This includes applications in agriculture, horticulture, industrial and household applications (eg dishwashing compositions or detergent tablets).

The substrate of the active ingredient-containing layer as well as the layer containing no active ingredient may contain the following components: polyisobutylene, esters of polyvinyl alcohol, polyacrylic acid, polymethacrylic acid and poly (methylmethacrylate) and Polymers such as derivatives thereof, natural rubber, styrene, isoprene, and resin components such as styrene, butadiene polymer or silicone polymer, saturated or unsaturated hydrocarbon resins, and derivatives of abiethyl alcohol and β-pinene; Plasticizers such as phthalic acid, triglycerides and fatty acids, and many other materials known to those skilled in the art.

All layers or individual layers, for example only the outermost layer or layers, can be designed to be resistant to gastric juice. This can be accomplished, for example, using waxes, sealing waxes, ethylcellulose or other materials known to those skilled in the art. Preferred embodiments are designed such that at least one layer is resistant to gastric juice. This may be at least one of the outermost or inner layers suitable for the intended use.

The layers of the dosage form according to the invention may contain, as additives, other adjuvants in addition to one or more active ingredients and a carrier material as a filler. These adjuvants are classified as plasticizers, thickeners, absorption accelerators, stabilizers or flow regulators depending on their function. Materials of this type must be physiologically acceptable and are generally known to those skilled in the art.

The materials used as carrier materials or fillers are those having suitable solubility, corrosiveness or swellability as necessary. Typical materials for this purpose include, for example, sugar alcohols such as lactose, celluloses, mannitol and sorbitol, various starches, alginic acid and the like.

Examples of coating materials that are soluble in gastric fluids include acrylic acid derivatives such as Eudragit L (trade name) and Eudrajit S (trade name), polyvinyl alcohol, hydroxypropylmethylcellulose acetate phthalate or cellulose acetate phthalate. Examples include Eudragit E30D (trade name), polyacrylic acid esters such as polyacrylic acid derivatives, celluloses such as cellac or methyl- or ethylcellulose.

To prepare the dosage forms according to the invention, the following methods may be usefully applied: spray coating, compression or sintering methods known to those skilled in the art, and lamination of individual layers to make a laminate, or to those skilled in the art for multiple coatings. Multiple coatings by known thermal melting or other methods. The process according to the invention represents a process by which a medicament of the invention having a concentric or sheet-like structure can be produced in a relatively simple manner by combining the processes of a suitable method.

1 shows a cross-sectional view of a centrally symmetric aspect of the present invention. In this case, the layer 2 containing no active ingredient is indicated in light color, and the active ingredient containing layer 1 is shown in dark color.

2 shows a cross-sectional view of an axisymmetric aspect of the present invention. In this case, the layer 2 containing no active ingredient is indicated in light color, and the active ingredient containing layer 1 is shown in dark color.

3 shows a cross-sectional view of an axisymmetric aspect of the present invention in which all layers are in contact with the surrounding medium through their edge surfaces. The layer 2 containing no active ingredient is shown in light color, and the active ingredient containing layer 1 is shown in dark color.

Fig. 4 shows a sheet-like laminate in which an active ingredient A-containing layer 1 and a plurality of layers 2 containing no active ingredient A are alternately formed. 4A shows a side view (section view) of a laminate having an optional water-impermeable layer on its edge surface, and FIG. 4B shows a plan view of an embodiment having geometrically different designs.

Figure 5 shows a cross-sectional view of a centrally symmetric aspect of the present invention in which layers containing no active ingredient and active ingredient containing layers are alternately arranged. The layer 2 containing no active ingredient is shown in light color, the active ingredient containing layer 1 is shown in dark color, and the layer 3 is shown in black color.

Figure 6 shows a cross-sectional view of a centrally symmetric aspect of the present invention in which layers containing no active ingredient and active ingredient containing layers are not alternately arranged. The layer 2 containing no active ingredient is shown in light color, the active ingredient containing layer 1 is shown in dark color, and the layer 3 is shown in black color.

Claims (21)

Multi-layered drug for the pulsed controlled delivery of the active ingredient, The medicament has 5 to 60 layers, in which case the layers containing the first active ingredient are alternately placed on adjacent layers not containing the first active ingredient, and the 5 to 60 layers are A multi-layered drug for pulsed controlled delivery of an active ingredient, which is arranged concentrically around a core which is the innermost layer of the 60 layers. The method of claim 1, The active ingredient, characterized in that some of the layers that do not contain the first active ingredient, or all of the layers that do not contain the first active ingredient, are configured to dissolve or corrode more slowly than the layer containing the first active ingredient. Multi-layered drug for controlled delivery in pulsed form. The method according to claim 1 or 2, The layer containing the first active ingredient is designed as a rapidly decomposing, corroding or dissolving layer containing a carrier substance or filler that accelerates the decomposition, corrosion or dissolution of the layer. A multi-layered drug for pulsed controlled delivery of the active ingredient. delete delete The method of claim 1, The agent is characterized in that it has a spherical or axisymmetric form, multi-layered drug for pulsed controlled delivery of the active ingredient. The method of claim 1, Wherein said first active ingredient is nicotine, the multi-layered drug for pulsed controlled delivery of the active ingredient. The method of claim 1, Wherein said first active ingredient is aspirin, a multi-layered drug for pulsed controlled delivery of the active ingredient. delete The method of claim 1, Multilayer medicament for pulsed controlled delivery of an active ingredient, characterized in that two layers which do not contain the first active ingredient are present between the layers containing the first active ingredient. The method of claim 1, At least one layer contains the first active ingredient and other additional active ingredients, or several of the active ingredients, alone or in combination, wherein the multilayered pharmaceutical agent for pulsed controlled delivery of the active ingredient. The method of claim 1, And wherein said layer free of said first active ingredient is free of said active ingredient. The method of claim 1, Wherein the medicament has active ingredient-containing layers that differ from each other in terms of concentration of the active ingredient. The method of claim 1, The medicament is a multi-layered medicament for pulsed controlled delivery of the active ingredient, characterized in that the layer having a different thickness and the thickness of the other layer. The method of claim 1, The medicament is a multi-layered medicament for pulsed controlled delivery of the active ingredient, characterized in that the form of a dummy (dummy), aspirable tablets, film coated tablets, uncoated tablets or sugar coated tablets. The method of claim 1, The individual layer further comprises spices, colorants, degradation accelerators, absorption accelerators or sweeteners, whether or not the active ingredient is contained, multi-layered drug for pulsed controlled delivery of the active ingredient. Claim 1, 2, 6, 7, 8, 10, 11, 12, 13, 14, 15 or 16. According to claim, The medicament has a layer designed to withstand gastric fluid, wherein the medicament is a multilayered medicament for pulsed controlled delivery of the active ingredient. Claim 1, 2, 6, 7, 8, 10, 11, 12, 13, 14, 15 or 16. As a method of manufacturing the medicament according to claim, After forming the core initially and then moving to a spray coating system, the layers containing the first active ingredient and the layer containing the first active ingredient are alternately coated, then packed alone or together, concentric A pharmaceutical manufacturing method, characterized in that for producing a tablet having. delete The multi-layered drug according to claim 1, wherein the drug is in the form of a prolate, ellipsoidal or cylindrical form. The multi-layered drug for pulsed controlled delivery of the active ingredient according to claim 1, wherein the drug has an outermost layer designed to withstand gastric juice.

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