Limiting deallylation of naloxone during storage of naloxonholdig depot

专利摘要:
The present invention relates to a packaged drug comprising a pharmaceutical depot formulation of naloxone or a pharmaceutically acceptable salt thereof and a package; use of a pharmaceutical depot formulation for obtaining a storage stable drug, comprising packaging a depot formulation of naloxone or a pharmaceutically compatible salt thereof; use of a package for storage stabilization of a drug comprising a pharmaceutical depot formulation of naloxone or a pharmaceutically compatible salt thereof; and use of a package for limiting deallyylation of naloxone or its pharmaceutically acceptable salt during storage of a pharmaceutical depot formulation of naloxone or a pharmaceutically compatible salt thereof.
公开号:DK201600098U1
申请号:DK201600098U
申请日:2016-09-02
公开日:2016-12-09
发明作者:Jiri Kubecek；Klaus Neuer；Andrea Andres
申请人:Acino Pharma Ag；
IPC主号:

专利说明:

The present invention relates to a packaged drug comprising a pharmaceutical formulation of naloxone or a pharmaceutically acceptable salt thereof and a package; use of a depot formulation of naloxone or a pharmaceutically compatible salt thereof to obtain a stable drug comprising packaging of the depot formulation; use of a package for storage stabilization of a medicament comprising a pharmaceutical depot formulation of naloxone or a pharmaceutically compatible salt thereof; and the use of a package for limiting deallylation of naloxone or its pharmaceutically acceptable salt during storage of a pharmaceutical depot formulation of naloxone or a pharmaceutically acceptable salt thereof.
Custody formulations play a key role in the development of improved therapies. They allow controlled and controlled release of the active substance over an extended period of time (typically 2 to 24 hours). This reduces the frequency of intake of the drug for the patients and increases the intake stability (compliance). For example, by means of depot formulations, treatment can be continued overnight without interrupting the patient's sleep. An additional benefit of oral formulations, particularly in the treatment of opioids / analgesics, is that they allow very regular concentrations of active substance in the blood, leading to less side effects and reducing the risk of developing addiction. In the prior art, various measures are known which allow the formulation of a drug form. It is common for these measures that the active substances are processed with adjuvants for shaped bodies, for example tablets or coated pills. The excipients thereby form a release or solution barrier for the active substance. Depending on the nature of the release barrier, different delaying methods can be distinguished. For example, there are osmotic systems, systems where the depot effect is caused by a coating, or systems in which the active substances are embedded in e.g. waxes, polymethacrylates, gels or silicic acids. This is the so-called matrix form.
Excipients used in the preparation of depot formulations may pose problems for the stability of the drug at longer storage times. This problem may, for example, concern certain alkaloid-based active substances, including in particular, some opioid agonists and opioid antagonists which fall into pain management. In particular, opioid agonists are characterized by a pain-relieving effect, while opioid antagonists may diminish or block the action or side effects of the opioid agonists. In particular, the problem relates to depot formulations of naloxone, an opioid antagonist common in the field of opioid pain therapy. Naloxone, due to its antagonizing effect, is used particularly to prevent in combination drugs with opioids a parenteral, euphoric effect of the opioid and thus parenteral abuse of the opioid (see also US 3773995 and US 3966940). In addition, naloxone can also be used to limit side effects of opioids such as constipation (see also N.P. Sykes, "Oral naloxone in opioid-associated constipation", The Lancet 1991, 337, p. 1475, and A. T. Skarin, "Cancer Pain Management; II" Oncology 2000, 5, pp. 1-12). The currently available tablets containing oxycodone hydrochloride and naloxone hydrochloride are offered under the trademark Tar-gin®. DE 102 15 131 A1 and DE 102 15 067 A1 relate to storage stable pharmaceutical oxycodone / naloxone formulations in a diffusion matrix. Hereby, the problem of the storage stability of the formulation is usually solved by the use of appropriate amounts of ethyl cellulose as matrix forming material, which leads to formulations which are themselves storage stable.
However, naloxone-containing pharmaceutical depot formulations which do not contain ethyl cellulose typically do not exhibit any storage stability per se like the formulations of DE 102 15 131 A1 and DE 102 15 067 A1.
Thus, with respect to pharmaceutical depot formulations of naloxone which do not, as the formulations of DE 102 15 131 A1 and DE 102 15 067 A1, exhibit storage stability themselves, the development of strategies for storing them under standard conditions is required, without the release profile of the active substance from the depot formulation or active substance content changes as a result of storage.
Within the scope of the present invention, it was found that naloxone is particularly widely degraded to noroxymorphone derived from naloxone by deallylation, using a matrix-forming polymer or copolymer (e.g., a polymethacrylate such as poly (ethyl acrylate). co-methylmethacrylate-co-trimethylammonium-ethylmethacrylate chloride) in the preparation of a naloxone-containing pharmaceutical formulation, under subsequent storage of the formulation itself under standard conditions.Naloxone degradation during storage can, surprisingly, be limited by a reduced water content, With a suitable packaging of the depot formulation, without being bound by theory, it is believed that naloxone is deallylated to noroxymorphone and that this degradation reaction requires the presence of water.
Accordingly, the naloxone degradation problem in depot formulations during storage is solved by the provision of a packaged drug, comprising a) a pharmaceutical depot formulation, wherein the pharmaceutical depot formulation comprises naloxone or a pharmaceutically acceptable salt thereof, oxycodone or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof and elongated release of naloxone or the pharmaceutically compatible salt thereof, and b) a package which is a blister pack comprising a molding film and a covering film wherein the molding film and the covering film exhibit a water vapor permeability of <3.0 g / (m2-d) independently of one another. .
Alternatively, the problem of the invention is solved by providing a packaged drug comprising a) a pharmaceutical depot formulation, wherein the pharmaceutical depot formulation comprises naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary agent for elongated release of naloxone or the pharmaceutically acceptable salt thereof, (b) a package which is a container of closure, the container of closure comprising a desiccant.
The problem is further solved according to the invention by using a pharmaceutical depot formulation containing naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary agent for elongated release of the naloxone or pharmaceutically acceptable salt thereof, to obtain a storage stable drug, the use of which comprises packaging the depot formulation in a blister pack comprising a molding film and a covering film, wherein the molding film and the covering film independently exhibit a water vapor permeability of <10 g / (m2-d).
Alternatively, the problem of the invention is also solved by using a pharmaceutical depot formulation containing naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary agent for elongated release of the naloxone or pharmaceutically acceptable salt thereof, to obtain a storage stable drug, the use of which comprises packaging. of the depot formulation in a closed container, the closed container comprising a desiccant.
The problem is also solved by using a package for storage stabilization of a medicament comprising a pharmaceutical depot formulation containing naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary agent for the prolonged release of the naloxone or the pharmaceutically acceptable salt thereof, wherein the package is a blister pack comprising a molding film and a covering film, wherein the molding film and the covering film independently exhibit a water vapor permeability of <10 g / (m2-d).
Alternatively, the problem of the invention is solved by using a package for storage stabilization of a medicament comprising a pharmaceutical depot formulation containing naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the sustained release of the naloxone or pharmaceutically acceptable salt thereof, the packaging being a closure container, the closure container comprising a desiccant.
Furthermore, the problem of the invention is also solved by using a package for limiting deallylation of naloxone or a pharmaceutically acceptable salt thereof in a pharmaceutical depot formulation containing naloxone or the pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the sustained release of the naloxone or pharmaceutically compatible salt thereof, during its storage, the packaging being a container of closure, the container of closure comprising a desiccant.
In addition, the problem of the invention is also solved by using a package for limiting deallylation of naloxone or a pharmaceutically acceptable salt thereof in a pharmaceutical depot formulation containing naloxone or the pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the elongated release of the naloxone or pharmaceutically compatible salt thereof, during its storage, wherein the packaging is a blister pack comprising a molding film and a covering film, the molding film and the covering film exhibiting a water vapor permeability of <10 g / (m2-d) independently of one another.
The term "drug" as used in the context of the present invention denotes a drug suitable for administration. Within the scope of the present invention, the drug is a pharmaceutical depot formulation. The pharmaceutical formulation and packaging together form the "packaged drug" according to the invention.
The term "pharmaceutical" as used in the context of the present invention means to elicit a therapeutic effect which can be used in the treatment or prevention of a disease or resulting pain in a patient.
The term "active substance" as used in the context of the present invention refers to the substance by which a therapeutic effect is elicited, which can be used in the treatment or prevention of a disease or resulting pain in a patient. Within the scope of the present invention, unless otherwise indicated, the active substance is naloxone or a pharmaceutically compatible salt thereof.
The term "formulation" as used in the context of the present invention is understood to mean a form of administration of a pharmaceutically active substance, in particular of naloxone or a pharmaceutically acceptable salt thereof, with a view to enabling an optimally adapted provision for the particular use, distribution and distribution of the active substance. The term "formulation unit" as used in the context of the present invention denotes a single unit of the form of administration, for example a tablet.
The term "depot formulation" as used in the context of the present invention is understood to mean a formulation which, upon administration of the formulation, allows the release of the pharmaceutically active substance, in the present case naloxone or a pharmaceutically acceptable salt thereof, over a longer period of time compared to an immediate release formulation. In this connection, release of the active substance is preferred over a period of 2 to 24 hours, preferably 2 to 20 hours and particularly preferably 2 to 16 hours or 2 to 12 hours. In this connection, statutory guidelines must preferably be met. Within the scope of the present invention, by "depot formulation" is meant a solid pharmaceutical form for oral use, ie. a shaped body such as a tablet.
The release of the active substance over a longer period of time than in a formulation for immediate release of the active substance is also referred to in the context of the present invention as "elongated release" of the active substance. The elongated release enables the release of the active substance from the depot formulation at a rate that allows the blood concentration, for example, the blood plasma concentration of the active substance to remain within the therapeutically effective range, i.e. moves above the therapeutically effective minimum concentration but below toxic concentration, whereby a once or twice daily administration of the depot formulation is used. Preferably, an administration is used twice daily on the formulation of the deposit. The amount of active substance released from the pharmaceutical depot formulation per unit time is also referred to as "release profile" or "release ratio". Preferably, a period of 2 to 24 hours, preferably 2 to 20 hours, and especially preferably 2 to 16 hours or 2 to 12 hours is used. The measurement of the release profile is performed as described later.
The term "storage stability" as used within the scope of the present invention relates to the packaged drug, unless otherwise stated. In order to be "stock stable" within the meaning of the present invention, the drug must fulfill both of the following conditions i) and ii). (i) First, after storage of the drug for at least two years immediately after its preparation, the active ingredient of the pharmaceutical formulation, in the present case naloxone or a pharmaceutically acceptable salt thereof, must show a release profile at standard conditions (i.e. at room temperature (25 ° C) and 60% relative humidity) similar to that shown by measurement immediately after preparation of the depot formulation, ie. without packaging the repository formulation and without storage under standard conditions.
The permissible variation in the release ratio is determined by the fact that the amount of active substance released per unit time must not differ by more than ± 10%, preferably not more than ± 5%, on the basis of the active substance content stated in the package leaflet. from the release values measured immediately after preparation of the depot formulation, where a 24-hour period is preferably used to measure the release profile (see also EMEA specification ECH Topic Q 6 A from May 2000). For this purpose, the release profile of the active substance is measured immediately after preparation of the depot formulation, without packaging of the depot formulation and without storage under standard conditions, and times at which 20%, 50% and 80% of the active substance are released, are determined on the basis of the indicate on the package leaflet the active substance content (see also European Pharmacopeia, 5.17.1., Recommendations on Dissolution Testing). The measurement of the release profile is repeated after two years of storage of the drug under standard conditions. The deviations in the times to which 20%, 50% and 80% of the active substance were released by the measurement directly after preparation of the depot formulation shall not exceed ± 10%, preferably not more than ± 5%, on the basis of the active ingredient leaflet. Thus, a release of, for example, 50% at a time X, for example, after 10 hours, when measuring the release profile immediately after preparation of the depot formulation, means that when measuring the release profile after two years of drug storage, it is tolerable with a release of 40 to 60%. at this time X, preferably a release of 45 to 55%, based on the active substance content indicated on the packaging.
The release profile of the active substance in the depot formulation immediately after preparation of the formulation and after two years of storage of the drug is determined from the average of 6 measurements. Methods for determining the active substance release are defined in the USP (US Pharmacopoeia) and in the European Pharmacopoeia. Preferably, the release of active substances from a depot formulation is determined using a basket apparatus. The stirring speed is 100 rpm. The temperature of the test medium is 37 ° C. As a test medium, a phosphate buffer with a pH of 6.8 is used. The volume of the test medium is 900 ml. (ii) In addition to condition (i), the active substance content of the pharmaceutical formulation, in the present case, the naloxone or naloxone salt content of the formulation, after storage of the medicinal product for at least two years immediately after its preparation under standard conditions (ie at room temperature ( 25 ° C) and 60% relative humidity) should not differ by more than 5% from the original active substance content immediately after preparation of the depot formulation.
The content of the active substance in the pharmaceutical formulation is determined immediately after preparation of the formulation and after two years of storage of the drug under standard conditions based on, in each case, the average of 6 measurements. To this end, the active substance, in the present case, naloxone or a pharmaceutically compatible salt thereof, is extracted from the intact or mortar-supported formulation with a suitable organic solvent and the extract is quantitatively analyzed by liquid chromatography, for example HPLC with UV detection.
In the case of a "stock stable drug", within the scope of the present invention, it is preferably a pharmaceutical storage formulation for which storage stability according to the above definitions (i) and (ii) is obtained using a packaging and storing the storage formulation in a packaging. Storage stable drugs within the meaning of the present invention, upon removal of the packaging and immediate determination of the release profile of (i) and of the active substance content of (ii), show measurement values within the limits set out in (i) and (ii).
By "inherently stock stable" is meant within the context of a present invention such depot formulations which, by themselves, thus, because of their composition, fulfill both of the above requirements (i) and (ii) as, for example, those of DE 102 15 131 A1 and DE 102 15 067 All described formulations. Inventory-stable pharmaceutical repository formulations fulfill requirements i) and ii) even when not stored in a package described under the present invention under standard conditions. While storing the pharmaceutical depot formulation described in the present invention in a package, no storage stability per se is achieved.
By "storage stabilization" of a drug, according to the present invention, it is meant that the drug, by means of suitable packaging, becomes more stable during storage. For this purpose, both the unpackaged and the packaged drug are determined immediately after manufacture of the drug as well as after a certain shelf life, e.g. after two years, (i) the release profile of the active ingredient in the pharmaceutical formulation, and (ii) the content of active substance in the pharmaceutical formulation. Preferably, the storage is carried out under standard conditions (25 ° C, 60% relative humidity), for example for two years. Alternatively, the storage can also be made e.g. at (a) 21 ° C, 45% relative humidity; (b) 30, 35% relative humidity; (c) 30 ° C, 65% relative humidity; (d) 30 ° C, 75% relative humidity; or (e) 40 ° C, 75% relative humidity, in each case, for example, for two years. The release profile as well as the content of the active substance are, for this reason, calculated locally as explained under the term "storage stability". Inventory stabilization of a drug by appropriate packaging then occurs when (i) the release profile and / or (ii) the active substance content of the pharmaceutical depot formulation changes less in the packaged drug than in the unpackaged drug.
By "restriction" of deallyylation of naloxone or the pharmaceutically acceptable salt thereof in a depot formulation according to the preparation during its storage using a packaging is meant that the deallylation of naloxone or the pharmaceutically compatible salt proceeds more slowly in the packaged depot formulation during its storage, f. eg. over two years, than in the corresponding unpackaged deposit formulation. The storage is preferably carried out under standard conditions (25 ° C, 60% relative humidity), for example for two years. Alternatively, the storage can also be made e.g. at (a) 21 ° C, 45% relative humidity; (b) 30, 35% relative humidity; (c) 30 ° C, 65% relative humidity; (d) 30 ° C, 75% relative humidity; or (e) 40 ° C, 75% relative humidity, in each case, for example, for two years. For this purpose, the content of noroxymorphone (salt), ie. the degradation product from the deallylation, in the naloxone (salt) -containing and packaged storage form after storage thereof.
To determine the content of the naloxone (salt) containing pharmaceutical depot formulation of noroxymorphone (salt), an amount of this degradation product contained in a subsample is extracted, i.e. a suitable sub-portion, a mixture of 20 mortar-molded formulations, with a suitable organic solvent, and the extract is quantitatively analyzed by liquid chromatography, e.g. HPLC with UV detection.
The term "water vapor permeability" as used within the scope of the present invention denotes the basic permeability of a package to water vapor. The smaller the water vapor permeability of a package, the less moisture reaches from its surroundings to the interior of the package. The water vapor permeability is determined according to DIN 53122-1 / DIN 53122-A or DIN 53122-2 / DIN53122-2-A. For this, a sample is used which preferably has a measuring surface of 100 cm 2 and a defined thickness, for example 5 to 500 µm. A sample container filled with desiccant is enclosed by the sample and subjected to a defined sample climate. The amount of water penetrating the sample is determined by weighing (procedure according to DIN 53122-1 / DIN 53122-A). Alternatively, the sample is built into a permeation cell to form a barrier between two secluded chambers. A tempered measuring chamber is rinsed with a carrier gas of defined humidity. The water passing through the sample is transported to the second chamber with a flushing gas to the detector, where the concentration is determined from which the water vapor permeability can be calculated (method according to DIN 53122-2 / DIN 53122-2-A). The water vapor permeability is determined according to the expected permeability of the material.
The term "desiccant" as used in the context of the present invention refers to chemical compounds which extract water. The water may be chemically bonded, for example, using water-extracting compounds such as calcium chloride, or the drying may be by adsorption, for example using silica, molecular sieve or bentonite.
The term "ethyl cellulose-free" or "free of our ethyl cellulose" as used within the scope of the present invention means that the pharmaceutical depot formulation of the present invention contains substantially no ethyl cellulose. This means that the pharmaceutical depot formulation comprises less than 1% by weight of ethyl cellulose.
The term "weight percent" or "% by weight" as used in the context of the present invention denotes the percentage by weight of a component of the pharmaceutical depot formulation on the basis of the total weight of the formulation, unless otherwise stated or obvious under the circumstances.
The term "bioequivalent" or "bioequivalence" as used within the scope of the present invention means any differences with respect to the plasma mirror-time curve (area under the curve (AUC)), Cmax (maximum plasma concentration) and tmax (time of the maximum plasma concentration) for two drugs with the same active substance with sufficient probability is within the bioequivalence range. With regard to the drugs with the same active substance, these are test product (generic) and reference product (original product). Specifically, test product and reference product are considered bioequivalent when the AUC, Cmax and tmax of the test product correspond to the same values of the reference product within a 95% confidence interval.
Fig. 1 shows the oxycodone hydrochloride (OxyHCI) release profile from a preparation formulation of the preparation containing 40 mg / 20 mg oxycodone hydrochloride / naloxone hydrochloride (test product) compared to the oxycodone hydrochloride (OxyHCI) release profile of the corresponding 20 mg / product product oxycodone hydrochloride / naloxone hydrochloride, in each case at a pH of 6.8 (Basket apparatus, stirring speed of 100 rpm).
FIG. 2 shows the oxycodone hydrochloride (OxyHCI) release profile from a preparation formulation of the preparation containing 5 mg / 2.5 mg oxycodone hydrochloride / naloxone hydrochloride (test product) in comparison with the oxycodone hydrochloride (OxyHCI) release profile of the corresponding reference product 5 mg oxycodone hydrochloride / naloxone hydrochloride, in each case at a pH of 6.8 (Basket apparatus, stirring speed of 100 rpm).
The present invention relates to a [1] packaged drug, comprising a) a pharmaceutical depot formulation, wherein the pharmaceutical depot formulation comprises naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the prolonged release of naloxone or the pharmaceutically acceptable salt thereof, and b a package which is a blister pack comprising a molding film and a covering film, wherein the molding film and the covering film independently exhibit a water vapor permeability of <3.0 g / (m2-d); a [2] packaged drug according to item 1, wherein the molding film consists of a material comprising at least one polymer or aluminum and / or the covering film consists of a material comprising aluminum; a [3] packaged drug according to paragraph [2], wherein the at least one polymer is selected from the group consisting of PVC, PVdC, PE, PET, PP and COC; a [4] packaged drug according to one of paragraphs [1], [2] and [3], wherein the blister pack is a push-through pack, pull-off pack or pull-through push pack; a [5] packaged drug comprising a) a pharmaceutical depot formulation, wherein the pharmaceutical depot formulation comprises naloxone or a pharmaceutically acceptable salt thereof, oxycodone or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable auxiliary agent for the prolonged release of naloxone or the pharmaceutically acceptable salt. and (b) a package which is a container of closure, the container of closure comprising a desiccant; a [6] packaged drug according to paragraph [5], wherein the container and closed independently exhibit a water vapor permeability of <10.0 g / (m2-d); a [7] packaged drug according to one of points [5] and [6], wherein the container and closed independently consist of a material selected from the group consisting of LDPE, HDPE, PVC, PVdC, PP, polycarbonate, COC and PET; an [8] packaged drug according to one of points [5], [6] and [7], wherein the desiccant is selected from the group consisting of sodium sulfate, silica, molecular sieve (zeolite), alumina, calcium chloride, calcium oxide, potassium carbonate, copper sulfate, magnesium sulfate, magnesium oxide, bentonite or a mixture thereof; [9] packaged drug according to one of points [5], [6], [7] and [8], wherein the desiccant is in the container enclosure; a [10] packaged drug according to one of the preceding points, wherein the pharmaceutical depot formulation is free of ethyl cellulose; a [11] packaged drug according to one of the preceding points, wherein the pharmaceutical depot formulation comprises polymethacrylate, preferably cationic polymethacrylate; a [12] packaged drug according to one of the preceding points, wherein the pharmaceutical depot formulation is matrix-based and / or has a hydrophobic film-forming coating; [13] packaged drug according to one of the preceding points, wherein the pharmaceutical depot formulation is matrix-based and comprises at least one matrix-forming material as a pharmaceutically compatible excipient, wherein the at least one matrix-forming material is a polymethacrylate, in particular a cationic polymethacrylate, and wherein preferably further at least one fatty alcohol, for example stearyl alcohol, is included; a [14] packaged drug according to paragraph [13], wherein the pharmaceutical depot formulation comprises at least one polymethacrylate and at least one fatty alcohol in a weight ratio of 1: 3 to 1: 4 (polymethacrylate for fatty alcohol); a [15] packaged drug according to one of points [13] and [14], wherein the weight proportion of the sum of polymethacrylate and fatty alcohol in the pharmaceutical depot formulation is 25 to 40% by weight, preferably 30 to 35% by weight, in each case on the basis of the total weight of the depot formulation; a [16] packaged drug according to one of the preceding points, wherein the pharmaceutical depot formulation comprises at least one opioid agonist; a [17] packaged drug according to paragraph [16], wherein the opioid agonist is oxycodone or a pharmaceutically compatible salt thereof, wherein oxycodone is preferably present as a base or as hydrochloride, especially as hydrochloride; a [18] packaged drug according to paragraph [17] for the treatment of moderate to severe pain; a [19] packaged drug according to one of the preceding points, wherein the pharmaceutical depot formulation further comprises fillers, carriers, binder, granulating agent, lubricant, lubricant, dyes, plasticizer, preservative, abrasive and / or flavoring agents; a [20] packaged drug according to one of the preceding points, wherein the pharmaceutical depot formulation is available as (multilayer) tablet, coated tablet, capsule, granule or powder; and a [21] packaged drug according to one of the preceding points, wherein the pharmaceutical depot formulation is not storage stable without the packaging.
The invention further relates to [22] use of a pharmaceutical depot formulation as defined in paragraph [21] for obtaining a stock-stable drug, which use comprises packaging the depot formulation in a blister pack comprising a molding film and a covering film, wherein the molding film and the covering film independently exhibit a water vapor permeability of <10 g / (m2-d); and [23] using a pharmaceutical depot formulation as defined in paragraph [21] for obtaining a storage stable drug, said use comprising packaging the depot formulation in a closed container, said closed container comprising a desiccant. In a further aspect, the present invention relates to the use of a pharmaceutical depot formulation containing naloxone or a pharmaceutically compatible salt thereof to obtain a stock stable drug by packaging. The packaging serves to protect the deposit formulation from moisture. Thanks to the protection against humidity, a stable drug can be obtained despite the renunciation of ethyl cellulose.
The invention further relates to [24] the use of a package for storage stabilization of a medicament, wherein the medicament comprises a pharmaceutical depot formulation as defined in any of points [1] to [21], and wherein the packaging is a blister pack comprising a molding film and a covering film, wherein mold film and cover film independently exhibit a water vapor permeability of <10 g / (m2-d); and [25] using a packaging for storage stabilization of a medicament, wherein the medicament comprises a pharmaceutical depot formulation as defined in any of points [1] to [21], and the packaging is a closure container, wherein the closure container comprises a desiccant. . Accordingly, in a further aspect, the present invention relates to the use of a package for storage stabilization of a drug comprising a pharmaceutical depot formulation containing naloxone or a pharmaceutically compatible salt thereof. The packaging serves to protect the storage formulation from moisture and thus also serves to stabilize it during storage.
The invention further relates to the use [26] of a package for limiting deallyylation of naloxone or its pharmaceutically acceptable salt in a pharmaceutical depot formulation as defined in one of points [1] to [21] during its storage, wherein the package is a container with closure the closure container comprising a desiccant; [27] use of a package for limiting deallyylation of naloxone or its pharmaceutically acceptable salt in a pharmaceutical depot formulation as defined in one of points [1] to [21] during its storage, wherein the packaging is a blister pack comprising a molding film and a cover film wherein molding film and cover film independently exhibit a water vapor permeability of <10 g / (m2-d); [28] use according to one of points [26] and [27], wherein the pharmaceutical depot formulation contains polymethacrylate, preferably cationic polymethacrylate, preferably cationic copolymer of ethyl acrylate, methyl methacrylate and methacrylic acid ester with quaternary ammonium group, in particular poly (ethyl acrylate co-methyl). -co-trimethylammonium-ethyl methacrylate salt) such as e.g. poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonium-ethyl methacrylate chloride), and [29) use according to item [28], wherein the weight ratio of ethyl acrylate, methyl methacrylate and methacrylic acid ester with quaternary ammonium group is 1: 2: 0.2 or 1: 2: 0.1. In a further aspect, the present invention relates to the use of a package for limiting deallylation of naloxone or the pharmaceutically acceptable salt thereof in a pharmaceutical depot formulation containing naloxone or a pharmaceutically acceptable salt thereof during storage thereof. In the following, the production will be described in detail.
Within the scope of the present invention, it was found that storage of a pharmaceutical depot formulation as described within the scope of the present invention in a package as described within the scope of the present invention enables storage of a pharmaceutical depot formulation of naloxone or a pharmaceutically compatible salt thereof. , eg. for at least two years under standard conditions, without changing the release profile of the active substance and / or the active substance content in the pharmaceutical formulation. Pharmaceutical depot formulation and packaging, as described in the context of the present invention, together form the packaged drug of the manufacture which is storage stable in the sense as defined in definitions (i) and (ii) above.
Preferably, the pharmaceutical depot formulations of the present invention are depot formulations which are not in themselves storage stable, that is, such depot formulations which, at least at one point, are not in themselves, i.e. as a result of their composition, the above definitions (i) and (ii) satisfy stock stability. Due to the effect of water, water vapor or humidity in general, these uncoated storage formulations are not storage stable so that the content of the active substance in the formulation is reduced by chemical degradation of the active substance and / or the release profile of the active substance from the storage form changes, when storing the repository formulation without packaging under standard conditions.
By storing the depot formulation as described within the scope of the present invention in a package as described within the scope of the present invention, storage of the formulation is allowed under standard conditions without exceeding the release ratio of the active substance and / or the content of activist substance in the formulation. the limit values laid down in the above definitions (i) and (ii). Accordingly, the storage of the pharmaceutical storage formulation in a package as described within the scope of the present invention enables the provision of a stock stable drug according to the manufacture. Without the packaging, the pharmaceutical storage formulation as described in the context of the present invention is preferably not storage stable.
The pharmaceutical depot formulation of the present invention comprises naloxone or a pharmaceutically compatible salt thereof as a pharmaceutically active ingredient. Naloxone can be used in the form of free base or as a pharmaceutically compatible salt, for example as hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, phosphate, malate, maleate, hydrobromide, hydroiodide, fumarate and succinate, the hydrochloride of naloxone. is preferred within the scope of the present invention. Naloxone hydrochloride is commonly used in the form of naloxone hydrochloride dihydrate. However, in the present invention, quantity indications regarding naloxone hydrochloride refer to the anhydrous form, and the same applies to any other active substance.
Naloxone or the pharmaceutically acceptable salt thereof is preferably contained in the pharmaceutical depot formulation of the present invention in an amount of 1 to 50% by weight based on the total weight of the formulation. Particularly preferred is an amount of 1 to 20% by weight, and especially an amount of 2 to 10% by weight, in each case on the basis of the total weight of the depot formulation.
The pharmaceutical depot formulation of the present invention preferably contains 1 to 100 mg, preferably 1 mg to 25 mg, naloxone or a pharmaceutically compatible all thereof, e.g. naloxone hydrochloride. Particularly preferred single doses are 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg.
The pharmaceutical depot formulation as described within the scope of the present invention comprises for elongated release of naloxone or the pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable excipient which affects the release profile of naloxone or the pharmaceutically acceptable salt thereof. Thus, the at least one pharmaceutically compatible excipient is a material which allows elongated release of the active substance in an aqueous medium.
Auxiliary elongated active release agents are common auxiliary agents commonly used in the field of pharmaceuticals, for example hydrophilic and hydrophobic polymers such as rubber, cellulose ether, acrylic resin, polymethacrylate, polyvinyl acetate and protein derivatives; substituted and unsubstituted fatty acids, fatty alcohols, fatty acid glycerine ester, mineral oils, vegetable oils, waxes and polyalkylene glycols.
Preferably, within the scope of the present invention, these are auxiliary agents which do not lead to an intrinsically stable pharmaceutical depot formulation as described in DE 102 15 131 A1 and DE 102 15 067. Particularly preferred as pharmaceutically compatible auxiliaries for elongated release of active substance is polymethacrylates, polyvinyl acetate and water swellable materials such as hydroxyalkylcellulose derivatives, for example HPMC. Pharmaceutical depot formulations within the meaning of the present invention, which include polymethacrylates or water-swellable materials as pharmaceutically compatible excipients, are not in themselves storage stable, ie. non-storage stable due to their composition, and cannot be stored under standard conditions without packaging, without changing the release profile of the active substance and / or the active substance content of the formulation.
Preferably, the pharmaceutical depot formulation of the present invention is free of ethyl cellulose. In a further preferred embodiment, the pharmaceutical depot formulation of the present invention contains less than 0.1% by weight of ethylcellulose, respectively. 0% by weight ethyl cellulose. Particularly preferred pharmaceutically compatible excipients within the scope of the present invention are polymethacrylates. The polymethacrylates may be neutral or cationic polymethacrylates. Also preferred is polyvinyl acetate.
The neutral polymethacrylates are preferably neutral copolymers of ethyl acrylate and methyl methacrylate (poly (ethyl acrylate-co-methyl methacrylate)), the weight ratio of ethyl acrylate to methyl methacrylate preferably being 2: 1. The molecular weight of the neutral polymethacrylates is preferably between 500,000 g / mol and 1,000,000 g / mol, especially between 600,000 g / mol and 750,000 g / mol. Particularly preferred are neutral polymethacrylates such as the aqueous dispersions Eudragit® NE 30 D, Eudragit® NE 40 D and Eudragit® NM 30D, which are available for purchase from Evonik Industries.
The cationic polymethacrylates are preferably cationic copolymers of ethyl acrylate, methyl methacrylate and methacrylic acid ester with quaternary ammonium group such as e.g. poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonium-ethyl methacrylate salts), especially poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonium-ethyl methacrylate chloride), the weight ratio of ethyl acrylate, methyl methacrylate and methacrylic acid ester group with quaternary acid ester with quaternary : 2: 0.2 or 1: 2: 0.1. The molecular weight of the cationic polymethacrylates is preferably between 20,000 g / mol and 50,000 g / mol, especially between 25,000 g / mol and 40,000 g / mol. Particularly preferred are cationic polymethacrylates such as the aqueous dispersions Eudragit® RS 30D and Eudragit® RL 30D, which are available for purchase from Evonik Industries.
The depot formulation as described within the scope of the present invention may contain 1 to 80% by weight of the at least one pharmaceutically acceptable excipient for elongated release of the active substance based on the total weight of the formulation. Preferred are 10 to 50% by weight and particularly preferred is 20 to 40% by weight of the at least one pharmaceutically acceptable excipient, in each case according to the total weight of the depot formulation.
Preferably, the pharmaceutical depot formulation of the present invention contains no gelatin capsule.
In addition to the type and weight ratio of excipients for elongated release of active substance, i. delay substances, the release profile of one or more of the active substances contained therein is particularly controlled by the use of water-soluble inert materials which do not extend the release. Without being bound by theory, it is believed that due to the presence of such materials, pores form in the depot formulation after placement of the depot formulation in an aqueous phase such as, for example, gastric juice, which pores lead to an increase in the release of one or more of the several active substances. Preferably, this material is lactose or lactose monohydrate.
The package described for the storage of the pharmaceutical depot formulation can, first, be a blister pack comprising a molding film and a covering film, the molding film and the covering film exhibiting a water vapor permeability of <3.0 g / (independently of one another). m2-d).
The molding foil is a packaging component which accommodates the drug, in the present case the pharmaceutical depot formulation, in chambers.
The molding sheet material preferably comprises at least one polymer (polymer-based molding film). The polymer is preferably a polymer film. As polymeric or polymeric film materials in particular, PVC (polyvinyl chloride), PVdC (polyvinyl dichloride), PE (polyethyl), PET (polyethylene terephthalate), PP (polypropylene) and COC (cycloolefin copolymers) are discussed. Such polymer-based molds can be obtained by thermoforms.
The molding film may consist of several layers of polymer film. Particularly preferred are polymer films which comprise layers of PVdC and PVC. Such polymer films may be commercially available under the designation "Duplex ™". Particularly preferred are polymer films which include layers of PVC, PE and PVdC. Such polymer films may be commercially available under the designation "Triplex ™"
The thickness of the polymer-based molding foil is preferably between 5 and 500 mm, particularly preferably between 10 and 400 µm, particularly preferably between 20 and 300 µm.
Alternatively to the polymer-based molding film as described above, molding film material may also comprise aluminum (aluminum-based molding film), a molding film being obtainable by cold forms of aluminum. The aluminum foil is preferably aluminum foil. The thickness of the aluminum-based molding film is preferably between 5 and 500 µm, particularly preferably between 10 and 400 µm, particularly preferably between 20 and 300 µm.
The water vapor permeability of the mold foil is preferably <2.5 g / (m2 * d), <2.0 g / (m2 »d), <1.5 g / (m2» d), particularly preferably <1.0 g / (m2 * d), <0.9 g / (m2 »d), <0.8 g / (m2 * d), <0.7 g / (m2» d), <0.6 g / (m2 »d) ), <0.5 g / (m2 »d), <0.4 g / (m2 * d), <0.3 g / (m2» d), <0.2 g / (m2 »d), and particularly preferably <0.1 g / (m 2 * d), wherein said water vapor permeability applies to both polymer-based molds and aluminum-based molds, and is affected for the polymer-based molding film by the polymers used. the number of layers and the thickness of the material, and in the case of the aluminum-based molding film, the thickness of the material.
The cover material is a support material which is connected to the mold foil by means of a sealing means, for example a heat seal varnish and encloses the mold foil chambers. The thickness of the cover material is preferably between 5 and 300 µm, particularly preferably between 10 and 200 µm, especially preferably between 20 and 100 µm.
The water vapor permeability of the cover material is preferably <2.5 g / (m2 * d), <2.0 g / (m2 »d), <1.5 g / (m2» d), particularly preferably <1.0 g / (m2 * d), <0.9 g / (m2 * d), <0.8 g / (m2 »d), <0.7 g / (m2» d), <0.6 g / (m2 * d) ), <0.5 g / (m2 * d), <0.4 g / (m2 »d), <0.3 g / (m2» d), <0.2 g / (m2 »d) and very preferably <0.1 g / (m2 »d), and is influenced by the thickness of the material and the constituents of the material.
Accordingly, the water vapor permeability of the molding film and the cover material, independently of each other, is preferably <2.5 g / (m2 »d), <2.0 g / (m2» d), <1.5 g / (m2 »d), particularly preferred < 1.0 g / (m2 »d), <0.9 g / (m2» d), <0.8 g / (m2 »d), <0.7 g / (m2» d), <0, 6 g / (m2 * d), <0.5 g / (m2 »d), <0.4 g / (m2» d), <0.3 g / (m2 »d), <0.2 g / (m2 »d), and most preferably <0.1 g / (m2» d).
The blister pack described in the context of the present invention is preferably a push-through pack, a pull-off pack or a pull-through push pack.
The compression pack comprises a molding film having at least one chamber in which is stored a formulation unit of the pharmaceutical depot formulation described in the present invention, e.g. a tablet. The chamber is sealed with the cover material. The formulation unit can be pressed through the cover material by applying pressure to the chamber and thus can be exposed for administration.
For example, the molding film may comprise an impression gasket of one or more polymer films which may, for example, consist of PVdC and PVC. For example, the cover material of the compression pack consists of aluminum foil. Alternatively, the foil gasket molding film may consist of aluminum and the aluminum foil cover material ("AI / AI gasket").
The cover pack comprises a molding film having at least one chamber in which is stored a formulation unit of the pharmaceutical depot formulation described in the present invention, e.g. a tablet. The chamber is sealed with cover material which in this case is peelable. When the cover material is pulled off, the formulation unit is exposed for administration.
The extraction penetration pack comprises a molding film having at least one chamber in which is stored a formulation unit of the pharmaceutical depot formulation described in the context of the present invention, e.g. a tablet. The chamber is sealed with the cover material. The cover material comprises at least two layers of different materials, one of the at least two layers can be removed by peel, and the formulation unit can be exposed for administration by printing through the remaining layers.
In addition to the protection of the deposit formulation against moisture, the pull-through packing gasket offers the advantage that access to the deposit formulation is difficult, thus providing protection against unauthorized access, for example from the children's side.
For example, the molding foil of the extraction gasket may consist of aluminum or at least one polymer film, for example a Duplex ™ or Triplex ™ film. Preferably, the extraction gasket molding foil consists of aluminum. The cover gasket cover material preferably comprises several layers. The outer layer may be a paper layer which is attached by means of an adhesive, for example a polyurethane-based adhesive, on a film layer, for example PET. The film layer is attached by means of an adhesive, for example on a polyurethane basis, to an aluminum layer, for example an aluminum foil which forms the inner layer and is connected to the molding film by means of a sealant. The formulation unit, for example in the form of a tablet, can be pushed through the aluminum layer after the peelable layers are removed.
Within the scope of the present invention, the blister pack is particularly preferably an alu-alu permeable gasket since it offers particularly good protection against moisture.
Also particularly preferred as a blister pack is a peel-through pressure pack, wherein the molding film is made of aluminum and the cover material is a multilayer system, the outer layer being a paper layer attached to a PET film layer using a polyurethane-based adhesive. The PET film layer is attached to an aluminum layer, for example, aluminum foil which forms the inner layer, by means of an adhesive, for example on a polyurethane basis. The formulation unit, for example in the form of a tablet, can be pushed through the aluminum layer after the peelable layers have been removed. Such a vent-penetration gasket enables a particularly low water vapor permeability and further protects the deposit formulation from unauthorized access, for example from the children's side.
The blister packs described within the scope of the present invention preferably comprise 5 to 20 chambers in which each formulation unit is stored, for example in the form of a (multilayer) tablet, a coating pellet, a capsule, a granule or a powder. For example, the blister pack comprises 6, 7, 8, 10, 12, 14, 16, 18 or 20 chambers, especially 10 or 14 chambers, above all 10 chambers.
Alternatively to the blister pack, the packaging described in the present invention for storing the pharmaceutical depot formulation described in the present invention is a container with a closure, the container with closure comprising a desiccant. The desiccant is selected from the group consisting of sodium sulfate, silica, molecular sieve (zeolite), alumina, calcium chloride, calcium oxide, potassium carbonate, copper sulfate, magnesium sulfate, magnesium oxide, bentonite or a mixture thereof. Especially preferred as a desiccant is silica. The desiccant allows the container to be opened and closed several times without destabilizing the deposit formulation contained therein, for example in the form of a tablet, by taking up water, water vapor or moisture in general. The desiccant is preferably located in the closure of the container. For this purpose, the closure preferably comprises a device for storing the desiccant.
The container closure preferably contains 100 mg to 5 g of the desiccant, more preferably 500 mg to 3 g, even more preferably 1 g to 2.5 g and especially 2g of the desiccant.
The container and sealed as described within the scope of the present invention preferably independently exhibit a water vapor permeability of <10.0 g / (m 2 * d). Particularly preferred is a water vapor permeability of <7.0 g / (m2 * d), <5.0 g / (m2 * d), <3.0 g / (m2 * d), <2.0 g / (m2 »d), <1.5 g / (m2 * d), <1.0 g / (m2» d), <0.9 g / (m2 * d), <0.8 g / (m2 * d), <0.7 g / (m2 »d), <0.6 g / (m2» d), <0.5 g / (m2 * d), <0.4 g / (m2 »d) ), <0.3 g / (m2 »d), <0.2 g / (m2 * d), and particularly preferred is a water vapor permeability of <0.1 g / (m2» d), each single case for container and close independently. The water vapor permeability of the container and closure is affected by the material of the container and closure.
The container preferably consists of a material which comprises LDPE ("low density polyethylene", low density polyethylene), HDPE ("high density polyethylene", high density polyethylene), PVC (polyvinyl chloride), PVdC (polyvinyl dichloride), PP (polypropylene), polycarbonate, PET ( polyethylene terephthalate) or a mixture thereof. Particularly preferred is a container of HDPE.
The container, for example, is a can or a bottle. It preferably contains 10 to 100 formulation units, for example in the form of a tablet. Preferably, it contains 10, 14, 20, 28, 30, 50, 56, 60, 98 or 100 formulation units. Preferred is a bottle which is particularly useful for storing (multi-layer) tablets, coating pills or capsules of the depot formulation described within the scope of the present invention.
The container closure serves for repeated opening and closing of the container. It can be designed as a swivel or foldable closure. Preferably, it is a (of) swivel closure.
The closure also consists of a material comprising LDPE, HDPE, PVC, PVDC, PP, polycarbonate, PET or a mixture thereof. Particularly preferred is a closure of HDPE.
Accordingly, the container and closure independently consist of a material comprising LDPE, HDPE, PVC, PVDC, PP, polycarbonate, PET or a mixture thereof.
The pharmaceutical depot formulation as described in the context of the present invention is preferably matrix-based and / or surrounded by a hydrophobic film-forming coating. Particularly preferred is a matrix-based repository formulation comprising at least one matrix-forming material as a pharmaceutically compatible auxiliary, causing an elongated release of naloxone or the pharmaceutically compatible naloxone salt.
Suitable matrix forming materials are those materials commonly used in the field of matrix-based deposit formulations, i.e. hydrophilic and hydrophobic polymers such as rubber, alkyl cellulose, hydroxyalkyl celluloses, cellulose ether, acrylic resins, polymethacrylates and protein derivatives; substituted and unsubstituted fatty acids, glycerine ester fatty acids, mineral oils, vegetable oils, waxes; and polyalkylene glycols, for example polyvinylpyrrolidone; hydroxycelluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, hydroxymethylcellulose, poly (vinyl) alcohols, polyvinyl acetate, alginates, hydrated hydroxyalkylcelluloses and hydroxypropylmethylcellulose; acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate copolymers, cyanoethyl methacrylates, aminoalkyl methacrylate copolymers, poly (acrylic acids), poly (methacrylic acids), polymethacrylates, poly (methyl methacrylics), poly (methyl methacrylics) ethyl cellulose, propyl cellulose; fatty alcohols such as lauryl, myristyl, stearyl, cetylstearyl, ceryl and / or cetyl alcohols, especially stearyl alcohol.
Within the scope of the present invention, such matrix forming materials are particularly preferred which do not lead to an intrinsically stable storage formulation of naloxone or a pharmaceutically compatible salt thereof as described in DE 102 15 131 A1 and DE 102 15 057 A1.
Preferably, the pharmaceutical depot formulation of the present invention is a matrix-based depot formulation which is free of ethyl cellulose. Particularly preferred is a matrix-based depot formulation comprising as matrix-forming material at least one polymethacrylate as well as at least one fatty alcohol, wherein the polymethacrylate is preferably a cationic polymethacrylate and / or the fatty alcohol is preferably stearyl alcohol. Among other things, by appropriately adjusting the amount ratios of the matrix forming materials, the release of naloxone or the pharmaceutically acceptable salt thereof from the matrix allows targeted control. Polymethacrylate and the fatty alcohol contained in a weight ratio of 1: 3 to 1: 4 (polymethacrylate for fatty alcohol). Particularly preferred is a weight ratio of polymethacrylate to fatty alcohol of 1: 3.3 to 1: 3.9. It was found that, under such a weight ratio of polymethacrylate to fatty alcohol, formulations suitable for administration once or twice a day were particularly well prepared.
The polymethacrylate, which is preferably a cationic polymethacrylate, is preferably contained in an amount of 4.0 to 10.0% by weight based on the total weight of the formulation. The fatty alcohol, which is preferably a stearyl alcohol, is preferably contained in an amount of 12.0 to 40.0% by weight based on the total weight of the formulation.
It was found that at a weight proportion of the sum of polymethacrylate and fatty alcohol of 25 to 40% by weight, preferably of 30 to 35% by weight, in each case on the basis of the total weight of the formulation, it is particularly well possible to prepare formulations which suitable for administration once or twice daily. Preferably, for this purpose, the polymethacrylate and fatty alcohol are present in a weight ratio of 1: 3 to 1: 4 (polymethacrylate to fatty alcohol), in particular 1: 3.3 to 1: 3.9.
If the weight fraction is reduced in a dosage formulation of the naloxone used or the pharmaceutically acceptable salt thereof, such as e.g. naloxone hydrochloride and / or the weight fraction of any further used active ingredient in the dosage formulation such as oxycodone or a pharmaceutically compatible salt thereof such as e.g. oxycodone hydrochloride, a comparable release profile for one or more active substances can be obtained at the various pH values, especially at pH <7, especially using a suitable amount of a water-soluble non-release extending inert material such as e.g. lactose or lactose monohydrate. Without being bound to the theory, it is believed that the deterioration of pore formation by the addition of aqueous medium to the depot formulation caused by the use of a smaller amount of active substance which affects the release can be balanced by increased pore formation caused by said inert material such as e.g. . lactose or lactose monohydrate. In particular, a comparable release profile for one or more active substances means that the release profile, measured as cumulative percentage release of active substance, does not differ by more than 20% absolute (percentage points), preferably by no more, in different weight proportions of active substance. more than 15% absolute, more preferably with no more than 10% absolute and especially with no more than 5% absolute. In this context, the release profile is determined as an average of 6 measurements. Methods for determining the active substance release are defined in the USP (US Pharmacopoeia) and in the European Pharmacopoeia. Preferably, the release is determined during the use of basketball apparatus. The stirring speed is 100 rpm. The temperature of the test medium is 37 ° C. As a test medium e.g. a phosphate buffer with a pH of 6.8 is used. The volume of the test medium is 900 ml.
Preferably, the amount of inert material used as described above, such as e.g. lactose or lactose monohydrate, based on the anhydrous form at least 50% by weight of the reduction of active substance, more preferably 55 to 100% by weight, even more preferably 60 to 90% by weight, in particular 65 to 80% by weight of the reduction of active substance. For example, reduced the amount of naloxone hydrochloride used in a depot formulation from 20 mg to 5 mg, then 50% by weight of the reduction of active substance corresponds to 7.5 mg.
Alternatively or in addition to using an inert material as described above, by reducing active substance, comparable release curves can be obtained at the various pH values, especially at pH <7, for example by (a) appropriately adjusting the proportion of expanding excipient in and / or (b) suitably adjusting the weight ratios of expanding excipients in the depot formulation if a supplementary excipient is used, for example, polymethacrylate and fatty alcohol.
Furthermore, by reducing active substance in the depot formulation, additional filler can be incorporated to approximately reach the initial weight of the depot formulation, ie. the weight before reducing active substance. In the present case, a non-storage stable storage formulation comprising naloxone or a pharmaceutically compatible salt thereof is formed, especially with polymethacrylates and fatty alcohols as matrix forming materials. Pharmaceutical depot formulations within the meaning of the present invention which contain polymethacrylates and / or fatty alcohols as matrix forming materials do not meet the above definitions of storage stability per se, ie. because of their composition.
The matrix-based repository formulation of the present invention can be obtained by conventional methods for preparing matrix-based repository formulations, for example by embedding naloxone or the pharmaceutically compatible naloxone salt into the matrix-forming material by melting, spray-drying, spray-drying, granulating, direct tableting.
Preferred is a process comprising the steps of: forming a granule of naloxone or a pharmaceutically acceptable salt thereof, the matrix forming material, and additional pharmaceutically compatible auxiliaries, for example by spray granulation, mixing the resulting granulate with additional pharmaceutically compatible auxiliaries as further described below, and optionally drying and pressing the granulate. The formation of the granulate is preferably done here by spray granulation with subsequent drying.
Alternatively, the matrix-based repository formulation can be prepared by extrusion, which is a cost-effective and efficient alternative to granulation.
Alternatively, or in addition to the matrix form, the pharmaceutical depot formulation disclosed within the scope of the present invention may comprise a hydrophobic film-forming coating affecting, respectively. controls and extends the release of naloxone or the pharmaceutically compatible naloxone salt.
This aspect becomes particularly relevant when naloxone or its pharmaceutically acceptable salt is provided in spheroids. Such spheroids typically exhibit a transverse dimension of 0.5 mm to 2.5 mm and preferably a transverse dimension of 0.5 mm to 2 mm. The spheroids comprise a material suitable for forming with the naloxone or a pharmaceutically compatible salt thereof into spheroids. In this connection, microcrystalline cellulose is preferred.
The spheroids comprise a hydrophobic film-forming coating comprising a pharmaceutically compatible excipient suitable for extending the release of naloxone or the pharmaceutically compatible naloxone salt. In addition, water-insoluble materials such as waxes, fatty alcohols, shellac, zein, water-insoluble cellulose, in particular ethyl cellulose or polymethacrylates, in particular Eudragit® polymethacrylates, are generally included as materials. The hydrophobic film-forming coating comprises at least one of the water-insoluble materials described above and may further contain water-soluble materials, for example, polyvinylpyrrolidone or hydroxypropylcellulose, to influence the release profile of the active substance. Within the scope of the present invention, a coating comprising auxiliaries which do not lead to an inherently storage-stable depot formulation is preferred.
Preferably, the depot formulation described in the present invention is in the matrix form.
In a preferred embodiment of the present invention, the pharmaceutical depot formulation further comprises at least one opioid agonist and / or an additional opioid antagonist as a pharmaceutically active active substance.
By opioid agonists is meant within the scope of the present invention all substances which belong to class NO2A of opioid analgesics according to WHO ATC classification and which propagate an analgesic effect after its use. By opioid antagonists is meant such substances which counteract the opioid agonists. Such substances can also be taken from the WHO ATC classification.
Preferred opioid agonists are preferably morphine, oxycodone, hydromorphone, propoxyphene, nicomorphine, dihydrocodeine, diamorphine, papaveretum, codeine, ethylmorphine, phenylpiperidine and derivatives thereof, methadone, dextropropoxyphene, buprenophen tilidine, tramadol, hydrocodone, dihydrocodeine, oxymorphone, fentanyl or sufentanyl or pharmaceutically compatible salts thereof. Particularly preferred are the opioid agonist oxycodone, hydrocodone, hydromorphone, morphine, codeine, dihydrocodeine, methadone, oxymorphone, fentanyl and sufentanyl or pharmaceutically compatible salts thereof. Quite particularly preferred as an opioid agonist is oxycodone or a pharmaceutically compatible salt thereof. Preferably, oxycodone is present as a base or as hydrochloride, especially as hydrochloride.
Preferred additional opioid antagonists are preferably naltrexone, nalmefene, nalorphine, nalbuphine, naloxonazines, methylnaltrexone, ketylcyclazocin, norbinaltorphimine, naltrindole, 6-3-naloxole, β-β-naltrexole or pharmaceutic. Particularly preferred minds are naltrexone and nalmefene or pharmaceutically compatible salts thereof as opioid antagonists. Particularly preferred is an embodiment wherein the pharmaceutical depot formulation of the present invention further comprises at least one opioid agonist, the opioid agonist being preferably oxycodone or a pharmaceutically compatible salt thereof, in particular oxycodone hydrochloride. Such depot formulations are preferably used to treat moderate to severe pain. Particularly preferred is an embodiment wherein the pharmaceutical depot formulation contains (i) naloxone base and oxycodone base or contains naloxone hydrochloride and oxycodone hydrochloride. The weight ratio of oxycodone base to naloxone base, respectively. oxycodone hydrochloride and naloxone hydrochloride in this connection are preferably 2: 1 to 20: 1, especially 2: 1. Custody formulations with such a weight ratio exhibit by regular, i.e. oral, use an analgesic effect, whereas parenteral abuse thereof leads to withdrawal symptoms (see also US 3,966,940 and US 3,773,955). Preferably, the formulations (i) and (ii) are used to treat moderate pain for severe pain and / or for second-line therapy of patients with severe to very severe ideopathic restless-leg syndrome. Particularly preferred is a formulation comprising oxycodone hydrochloride and naloxone hydrochloride in a weight ratio of 2: 1.
Preferably, the oral formulation contains 40 mg, 30 mg, 20 mg, 15 mg, 10 mg, 5 mg or 2.5 mg oxycodone and naloxone in an amount of 50% by weight of the oxycodone present at any given time. Also preferred is a prolonged-release formulation containing 40 mg, 30 mg, 20 mg, 15 mg, 10 mg, 5 mg or 2.5 mg oxycodone hydrochloride and naloxone hydrochloride in an amount of 50% by weight of the oxycodone hydrochloride present at any time. Said amounts of oxycodone hydrochloride and naloxone hydrochloride are also contained in tablets of the brand Targin®.
Preferably, the pharmaceutical repository formulation of (i) and / or (ii) is a matrix-based repository formulation which is free of ethyl cellulose. Particularly preferred are depot formulations (i) and (ii) which, as matrix forming material, comprise at least one polymethacrylate as well as at least one fatty alcohol, wherein the polymethacrylate is preferably a cationic polymethacrylate and / or the fatty alcohol is preferably stearyl alcohol. By an appropriate adjustment of the amount ratios of the matrix forming materials, the release of naloxone or naloxone hydrochloride and oxycodone respectively. oxycodone hydrochloride from the matrix itself is targeted. Polymethacrylate and the fatty alcohol are preferably comprised in a weight ratio of 1: 3 to 1: 4 (polymethacrylate for fatty alcohol). Particularly preferred is a weight ratio of polymethacrylate to fatty alcohol of 1: 3.3 to 1: 3.9. It was found that, under such a weight ratio of polymethacrylate to fatty alcohol, it is possible to produce particularly good formulations suitable for administration once or twice daily.
The polymethacrylate, which is preferably a cationic polymethacrylate, is preferably contained in a weight of 4.0 to 10.0% by weight based on the total weight of the formulation. The fatty alcohol, which is preferably a stearyl alcohol, is preferably contained in an amount of 12.0 to 40.0% by weight based on the total weight of the formulation.
It was further found that the depot formulations (i) and (ii) can be particularly well prepared as formulations suitable for administration once or twice daily when the weight fraction of the sum of polymethacrylate and fatty alcohol is 25 to 40% by weight, preferably 30% by weight. to 35% by weight, in each case based on the total weight of the formulation. In addition, if the polymethacrylate and fatty alcohol are present in a weight ratio of 1: 3 to 1: 4 (polymethacrylate to fatty alcohol), in particular of 1: 3.3 to 1: 3.9, depot formulations containing (i) can be prepared in this way. oxycodone and naloxone in a weight ratio of 2: 1 or (ii) oxycodone hydrochloride in a weight ratio of 2: 1 which are bioequivalent to Targin®. In these formulations, oxycodone, respectively. oxycodone hydrochloride preferably contained in an amount of 2 to 20% by weight, in particular 4 to 16% by weight, and naloxone, respectively. naloxone hydrochloride preferably in an amount of 1.0 to 10.0% by weight, especially 2 to 8% by weight, in each case on the basis of the total weight of the formulation. Preferred single doses of the 2: 1 weight ratio oxycodone hydrochloride / naloxone hydrochloride formulation include 40 mg oxycodone hydrochloride and 20 mg Naloxone hydrochloride, respectively. 20 mg oxycodone hydrochloride and 10 mg naloxone hydrochloride respectively. 10 mg oxycodone hydrochloride and 5 mg naloxone hydrochloride respectively. 5 mg oxycodone hydrochloride and 2.5 mg naloxone hydrochloride.
If in a dosage formulation containing oxycodone and naloxone respectively. oxycodone hydrochloride and naloxone hydrochloride, in each case in a 2: 1 weight ratio, as well as polymethacrylate and fatty alcohols as expanding excipients, reduction of the weight ratio of said active substances by unchanged weight ratio of said active substances, a comparable release profile of the active substances can be obtained. at the various pH values, especially at pH <7, especially using a suitable amount of a water-soluble non-release extending inert material such as e.g. lactose or lactose monohydrate. In particular, a comparable release profile for the active substances means that the release profile, measured as cumulative percentage release of active substance, does not differ by more than 20% absolute (percentage points), preferably by no more than 15% absolute, at different weight proportions of active substance. , more preferably with no more than 10% absolute and especially with no more than 5% absolute. In this context, the release profile is determined as an average of 6 measurements. Methods for determining the active substance release are defined in the USP (US Pharmacopoeia) and in the European Pharmacopoeia. Preferably, the release is determined during the use of basketball apparatus. The stirring speed is 100 rpm. The temperature of the test medium is 37 ° C. As a test medium e.g. a phosphate buffer with a pH of 6.8 is used. The volume of the test medium is 900 ml.
Preferably, the amount of inert material used as described above, such as e.g. lactose or lactose monohydrate, on the basis of the anhydrous form, at least 50% by weight of the total reduction of active substance, more preferably 55 to 100% by weight, even more preferably 60 to 90% by weight and in particular 65 to 80% by weight of the total reduction of active substance. By "the total reduction of active substance" in this context is meant the sum of the reduction of the active substances oxycodone and naloxone respectively. oxycodone hydrochloride and naloxone hydrochloride.
Alternatively or in addition to using an inert material as described above, by reducing active substance, comparable release curves can be obtained at the various pH values, especially at pH <7, for example by (a) appropriately adjusting the proportion of expanding excipient in the depot formulation (blend of polymethacrylate and fatty alcohol), and / or (b) appropriate adjustment of the weight ratios of polymethacrylate and fatty alcohol in the depot formulation.
Furthermore, by reducing active substance in the depot formulation, (additional) filler can be incorporated to approximately reach the original weight of the depot formulation, ie. the weight before reducing active substance.
Because comparable release curves can be obtained with the different contents of oxycodone and naloxone respectively. oxycodone hydrochloride and naloxone hydrochloride in the depot formulation using water-soluble non-release expanding intermaterials such as e.g. lactose or lactose monohydrate, by adjusting the weight ratio of expanding excipient (polymethacrylate and fatty alcohol) and / or by appropriately adjusting the weight ratio of polymethacrylate to fatty alcohol, depot formulations can be prepared for all dosage strengths of Tar-gin® with a weight fraction of the sum of polymethacrylate and fat alcohol of 25 to 40% by weight and a weight ratio of polymethacrylate to fat alcohol of 1: 3 to 1: 4, which are bioequivalent to a corresponding dose strength of Targin®.
The pharmaceutical depot formulation of the present invention preferably further comprises pharmaceutically compatible fillers, carriers, binders, granulating agents, lubricants, lubricants, colorants, plasticizers, preservatives, separators and / or flavorings common in the pharmaceutical formulation field.
The pharmaceutical depot formulation as described within the scope of the present invention may preferably contain 20 to 98% by weight of these materials on the basis of the total weight of the formulation. Particularly preferred is a content of 25 to 95% by weight and particularly preferred is a content of 30 to 90% by weight of these additional materials, in each case on the basis of the total weight of the pharmaceutical formulation.
As fillers may be used, for example, sugars such as lactose, lactose monohydrate, glucose or sucrose, starches and hydrolysates thereof, (microcrystalline) cellulose, cellactose, sugar alcohols such as sorbitol or mannitol, soluble calcium salts such as calcium hydrogen phosphate, dicalcium phosphate or tri-calcium phosphate. Preferably, microcrystalline cellulose and / or lactose is used. as monohydrate. The microcrystalline cellulose is preferably contained in an amount of 20.0 to 40.0% by weight based on the total weight of the formulation. Lactose or lactose monohydrate is preferably contained in an amount of 0 to 15.0% by weight based on the total weight of the formulation. In particular, as described above, lactose or lactose monohydrate can be used to adjust the release profile of the depot formulation.
Binders such as, for example, polyvinylpyrrolidone (Povidone) are preferably used in an amount of 1.0 to 9.0% by weight based on the total weight of the formulation.
Lubricants are, for example, magnesium stearate, calcium stearate, fatty acids such as stearic acids or fats such as hydrated American oil, polyethylene glycols or high-dispersion silicas (Aerosil®), with high-dispersion silicas (Aerosil®) being preferably used. Lubricants are preferably used in an amount of 0.1 to 1.5% by weight based on the total weight of the formulation.
Softeners such as, for example, triacetin are preferably used in an amount of 0.5 to 2.0% by weight based on the total weight of the formulation. After prolonged storage, the formulations may be used. exhibit some brittleness which may affect the release formulation of the depot formulation. By using softener in said amount, this problem can be solved.
Separators such as, for example, talc are preferably used in an amount of 1.5 to 4.0% by weight based on the total weight of the formulation.
The pharmaceutical depot formulation described in the present invention is intended for oral administration (administration). It may be available as a (multilayer) tablet, coated pill, capsule, granule or powder.
Preferably, it is available as a multilayer tablet. This exhibits a film-forming coating which preferably comprises hypromellose as a coating agent, polyethylene glycol as plasticizer and talc as a separating agent, wherein hypromellose is preferably contained in an amount of 1.0 to 4.5% by weight, polyethylene glycol preferably in an amount preferably 0.1 to 1.5% by weight and talc in an amount of 0.1 to 1.5% by weight, in each case based on the total weight of the multilayer tablet.
In addition, the coating may contain dyes selected, for example, from the group consisting of titanium dioxide, red iron oxide 30 E 172, yellow iron oxide 10 E 172 and FD &amp; C Blue or a mixture thereof. The (multilayer) tablet preferably has a weight between 100 and 300 mg, preferably between 120 and 260 mg.
Further, within the scope of the present invention, there is a process for producing a stock stable drug, the method comprising packaging a pharmaceutical depot formulation as described within the scope of the present invention in a blister pack comprising a molding film and a covering film, wherein molding film and cover film of each other exhibit a water vapor permeability of <10.0 g / (m2 »d).
The pharmaceutical depot formulation described in this process according to the preparation is the pharmaceutical depot formulation as described in connection with the packaged drug, i.e. a pharmaceutical depot formulation comprising naloxone or a pharmaceutically compatible salt thereof and at least one pharmaceutically acceptable auxiliary drug for extended release or naloxone. compatible salts thereof, and preferred embodiments as described above. In particular, the pharmaceutical storage formulation is preferably not storage stable without the packaging.
The water vapor permeability of the molding film described in the process of the invention preferably is <7.0 g / (m2 »d), <5.0 g / (m2» d), <3.0 g / (m2 »d), <2.0 g / (m2 * d), <1.0 g / (m2 »d), <0.9 g / (m2» d), <0.8 g / (m2 »d), <0 , 7 g / (m2 »d), <0.6 g / (m2» d), <0.5 g / (m2 »d), <0.4 g / (m2» d), <0.3 g / (m2 »d), <0.2 g / (m2» d), and particularly preferred is a water vapor permeability of <0.1 g / (m2 »d).
The water vapor permeability of the cover film described in the process of the invention preferably is <7.0 g / (m2 »d), <5.0 g / (m2 * d), <3.0 g / (m2» d), <2.0 g / (m2 ″ d), <1.0 g / (m2 ″ d), <0.9 g / (m2 ″ d), <0.8 g / (m2 ″ d), <0 , 7 g / (m2 »d), <0.6 g / (m2» d), <0.5 g / (m2 »d), <0.4 g / (m2» d), <0.3 g / (m2 »d), <0.2 g / (m2» d), and particularly preferred is a water vapor permeability of <0.1 g / (m2 »d).
Accordingly, the water vapor permeability of the molding film and the covering film described in the process according to the invention, independently of each other, preferably <7.0 g / (m2 »d), <5.0 g / (m2» d), <3.0 g / (m2 »d), <2.0 g / (m2» d), <1.0 g / (m2 * d), <0.9 g / (m2 »d), <0.8 g / (m2 * d), <0.7 g / (m2 »d), <0.6 g / (m2.d), <0.5 g / (m2» d), <0.4 g / (m2 ), <0.3 g / (m2 »d), <0.2 g / (m2» d), and particularly preferred is a water vapor permeability of <0.1 g / (m2 »d).
The water vapor permeability preform foil and cover foil are affected by the same factors that apply to the packaged drug described above. In addition, with respect to the blister pack described in the process of the manufacture comprising blister part and cover film, the same preferred embodiments as described in connection with the packaged drug apply.
Further, within the scope of the present invention, there is an alternative method for producing a stock stable drug, the method comprising packaging a pharmaceutical depot formulation as described within the context of the present invention in a container with a closure comprising a desiccant.
The pharmaceutical depot formulation described in the alternative process of the preparation is the pharmaceutical depot formulation as described in the context of the packaged drug, i.e. a pharmaceutical depot formulation comprising naloxone or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable auxiliary drug of extended release or pharmaceutically compatible salts thereof, and preferred embodiments as described above. In particular, the pharmaceutical storage formulation is preferably not storage stable without the packaging. The desiccant is the same desiccant as described in the context of the packaged drug, where silica is also preferred as desiccant.
The container and closed as described within the scope of the alternative method of production preferably independently exhibit a water vapor permeability of <10.0 g / (m 2 »d). Particularly preferred is a water vapor permeability of <7.0 g / (m2 »d), <5.0 g / (m2» d), <3.0 g / (m2 »d), <2.0 g / (m2 »D), <1.0 g / (m2 * d), <0.9 g / (m2» d), <0.8 g / (m2 »d), <0.7 g / (m2» d ), <0.6 g / (m2 »d), <0.5 g / (m2» d), <0.4 g / (m2 »d), <0.3 g / (m2» d), <0.2 g / (m2 »d), and particularly preferred is a water vapor permeability of <0.1 g / (m2» d), in each case independently of container and closure.
The water vapor permeability of the closure container described in the alternative process according to the manufacturing process is influenced by the same factors as the packaged drug described above.
The process of producing a stock-stable drug allows storage for at least two years under standard conditions, in particular of non-stock-stable pharmaceutical repository formulations, without the release profile of the active substance and / or the active substance content of the repository formulation changing beyond those of the present formulation. the storage stability definitions (i) and (ii) established limit values. Thus, in particular, storage of pharmaceutical repository formulations which do not inherently have storage stability is possible.
Within the scope of the present invention, it was further found that a package for storage stabilization of a drug comprising a pharmaceutical depot formulation as described within the scope of the present invention may be used, the package being a blister pack comprising a molding film and a cover film. wherein mold film and cover film independently exhibit a water vapor permeability of <10.0 g / (m2 »d).
The pharmaceutical depot formulation disclosed in this application of the invention is the pharmaceutical depot formulation as described in the context of the packaged drug, i.e. a pharmaceutical depot formulation comprising naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for extended release or pharmaceutically compatible salts thereof, and preferred embodiments as described above. In particular, the pharmaceutical storage formulation is preferably not storage stable without the packaging.
The water vapor permeability of the molding film described in the application of the invention preferably is <7.0 g / (m2 * d), <5.0 g / (m2 * d), <3.0 g / (m2 * d), <2.0 g / (m2 * d), <1.0 g / (m2 * d), <0.9 g / (m2 * d), <0.8 g / (m2 * d), <0 , 7 g / (m2 »d), <0.6 g / (m2 * d), <0.5 g / (m2 * d), <0.4 g / (m2 * d), <0.3 g / (m2 »d), <0.2 g / (m2 * d), and particularly preferred is a water vapor permeability of <0.1 g / (m2 * d).
The water vapor permeability of the cover film described in the application of the invention preferably is <7.0 g / (m2 * d), <5.0 g / (m2 »d), <3.0 g / (m2 * d), <2.0 g / (m2 * d), <1.0 g / (m2 * d), <0.9 g / (m2 * d), <0.8 g / (m2 * d), <0 , 7 g / (m2 »d), <0.6 g / (m2» d), <0.5 g / (m2 »d), <0.4 g / (m2» d), <0.3 g / (m2 »d), <0.2 g / (m2» d), and particularly preferred is a water vapor permeability of <0.1 g / (m2 »d).
Accordingly, the water vapor permeability of the molding film and the covering film described in the application of the invention, independently of one another, preferably <7.0 g / (m2 * d), <5.0 g / (m2 »d), <3.0 g / (m2 * d), <2.0 g / (m2 »d), <1.0 g / (m2 * d), <0.9 g / (m2» d), <0.8 g / (m2 * d), <0.7 g / (m2 »d), <0.6 g / (m2» d), <0.5 g / (m2 * d), <0.4 g / (m2 »d) ), <0.3 g / (m2 »d), <0.2 g / (m2» d), and particularly preferred is a water vapor permeability of <0.1 g / (m2 * d).
The water vapor permeability of the molding foil and the covering foil is affected by the same factors that apply to the packaged drug described above. Further, with respect to the blister pack described in the scope of use of the manufacture comprising the molding portion and the covering foil, the same preferred embodiments as described in the context of the packaged drug apply.
Further, within the scope of the present invention, it was found that an alternative packaging can be used for storage stabilization of a medicament comprising a pharmaceutical depot formulation described in the context of the present invention, wherein the packaging is a container of closure, wherein the container of closure comprises a desiccant. .
The pharmaceutical depot formulation described in the context of the use of an alternative packaging according to the invention is the pharmaceutical depot formulation as described in the context of the packaged drug, i.e., a pharmaceutical depot formulation comprising naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for extraction. naloxone or the pharmaceutically acceptable salt thereof, and preferred embodiments as described above. In particular, the pharmaceutical storage formulation is preferably not storage stable without the packaging. The desiccant is the same desiccant as described in the context of the packaged drug, where silica is also preferred as desiccant.
The container and closed as described within the scope of the alternative use according to the invention, independently of one another preferably exhibit a water vapor permeability of <10.0 g / (m 2 * d). Particularly preferred is a water vapor permeability of <7.0 g / (m2 »d), <5.0 g / (m2 * d), <3.0 g / (m2» d), <2.0 g / (m2 * d), <1.0 g / (m2 »d), <0.9 g / (m2 * d), <0.8 g / (m2» d), <0.7 g / (m2 * d) ), <0.6 g / (m2 * d), <0.5 g / (m2 * d), <0.4 g / (m2 »d), <0.3 g / (m2» d), <0.2 g / (m2 * d), and particularly preferred is a water vapor permeability of <0.1 g / (m2 * d), in each case independently of container and closure.
The water vapor permeability of the closure container described in the alternative application of the present invention is influenced by the same factors as the packaged drug described above. In addition, with respect to the container with closure, the same preferred embodiments as described in the context of the packaged drug apply.
The use according to the preparation of the packages described herein for storage stabilization of a medicament allows storage for at least two years under standard conditions, in particular of non-intrinsically stable pharmaceutical depot formulations, without changing the release profile of the active substance and / or the active substance content in the depot formulation. in addition to the limit values laid down in the storage stability definitions (i) and (ii). Thus, in particular, storage of pharmaceutical repository formulations which do not inherently have storage stability is possible.
Within the scope of the present invention, it was further found that a package for limiting deallylation of naloxone or a pharmaceutically compatible salt thereof in a pharmaceutical depot formulation described in the present invention may be used during its storage, e.g. for two years under standard conditions where the packaging is a blister pack comprising a molding film and a covering film, the molding film and the covering film independently exhibiting a water vapor permeability of <10.0 g / (m2 * d).
The pharmaceutical depot formulation disclosed in this application of the invention is the pharmaceutical depot formulation as described in the context of the packaged drug, i.e. a pharmaceutical depot formulation comprising naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for extended release or pharmaceutically compatible salts thereof, and preferred embodiments as described above. In particular, the pharmaceutical storage formulation is preferably not storage stable without the packaging.
The water vapor permeability of the molding film described in the application of the invention preferably is <7.0 g / (m2 * d), <5.0 g / (m2 * d), <3.0 g / (m2 * d), <2.0 g / (m2 »d), <1.0 g / (m2 * d), <0.9 g / (m2 * d), <0.8 g / (m2» d), <0 , 7 g / (m2 »d), <0.6 g / (m2 * d), <0.5 g / (m2» d), <0.4 g / (m2 * d), <0.3 g / (m2 »d), <0.2 g / (m2 * d), and particularly preferred is a water vapor permeability of <0.1 g / (m2 * d).
The water vapor permeability of the cover film described in the application of the invention preferably is <7.0 g / (m2 »d), <5.0 g / (m2» d), <3.0 g / (m2 * d), <2.0 g / (m2 »d), <1.0 g / (m2 * d), <0.9 g / (m2» d), <0.8 g / (m2 »d), <0 , 7 g / (m2 »d), <0.6 g / (m2 * d), <0.5 g / (m2» d), <0.4 g / (m2 »d), <0.3 g / (m2 * d), <0.2 g / (m2 »d), and particularly preferred is a water vapor permeability of <0.1 g / (m2» d).
Accordingly, the water vapor permeability of the molding film and the covering film described in the application according to the invention, independently of each other, preferably <7.0 g / (m2 »d), <5.0 g / (m2» d), <3.0 g / (m2 »d), <2.0 g / (m2» d), <1.0 g / (m2 »d), <0.9 g / (m2» d), <0.8 g / (m2 * d), <0.7 g / (m2 »d), <0.6 g / (m2» d), <0.5 g / (m2 »d), <0.4 g / (m2» d) ), <0.3 g / (m2 »d), <0.2 g / (m2» d), and particularly preferred is a water vapor permeability of <0.1 g / (m2 »d).
The water vapor permeability of the molding foil and the covering foil is affected by the same factors that apply to the packaged drug described above. Further, with respect to the blister pack described in the scope of use of the manufacture comprising the molding portion and the covering foil, the same preferred embodiments as described in the context of the packaged drug apply.
Further, within the scope of the present invention, it was found that an alternative package may be used to limit deallylation of naloxone or a pharmaceutically compatible salt thereof in a pharmaceutical depot formulation described herein within its storage, e.g. . for two years under standard conditions where the packaging is a closed container, the closed container comprising a desiccant.
The pharmaceutical depot formulation described in the context of the use of an alternative packaging according to the invention is the pharmaceutical depot formulation as described in the context of the packaged drug, i.e. a pharmaceutical depot formulation comprising naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary agent of or the pharmaceutically acceptable salt thereof, and preferred embodiments as described above. In particular, the pharmaceutical storage formulation is preferably not storage stable without the packaging. The desiccant is the same desiccant as described in the context of the packaged drug, where silica is also preferred as desiccant.
The container and closed as described within the scope of the alternative use according to the invention, independently of one another preferably exhibit a water vapor permeability of <10.0 g / (m 2 »d). Particularly preferred is a water vapor permeability of <7.0 g / (m2 »d), <5.0 g / (m2» d), <3.0 g / (m2 »d), <2.0 g / (m2 »d), <1.0 g / (m2» d), <0.9 g / (m2 »d), <0.8 g / (m2» d), <0.7 g / (m2 * d), <0.6 g / (m2 »d), <0.5 g / (m2 * d), <0.4 g / (m2 * d), <0.3 g / (m2» d) ), <0.2 g / (m2 »d), and particularly preferred is a water vapor permeability of <0.1 g / (m2» d), in each case independently of container and closure.
The water vapor permeability of the closure container described in the alternative application of the present invention is influenced by the same factors as the packaged drug described above. In addition, with respect to the container with closure, the same preferred embodiments as described in the context of the packaged drug apply.
The use according to the preparation of the packages described herein for limiting deallylation of naloxone or a pharmaceutically compatible salt thereof in a pharmaceutical depot formulation during its storage, e.g. in two under standard conditions, allows storage, in particular of non-intrinsically stable pharmaceutical repository formulations, for at least two years under standard conditions, without the release profile of the active substance and / or active substance content in the repository formulation changing beyond those in the storage stability definitions i) and (ii) established limit values. Thus, in particular, storage of pharmaceutical repository formulations which do not inherently have storage stability is possible.
Preferably, the packaged pharmaceutical formulation formulated as described in the context of the present invention contains less than 2% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight, and more preferably less than 0% by weight. , 2% by weight noroxymorphone (salt), in each case on the basis of the active substance content indicated on the package leaflet.
examples
Example 1
Preparation of Naloxone Hydrochloride-containing Tablets with EUDRAGIT® RS30D and Surelease® E-7-7050 (Comparison) as Matrix Forming Materials: The following amounts of the listed ingredients were used to prepare the tablets:
Nal-5-Eud Nal-5-Sure (Comparison from DE 102 15 131 Al)
Naloxone HCl: 5.0 mg 5.0 mg
Lactose Flow Lac 100: 74.25 mg 74.25 mg
Povidone 30: 5.0 mg 5.0 mg
Eudragit® RS30D: 10 mg solid
Surelease® E-7-7050: - 10 mg solid
Triacetin: 2.0 mg
Stearyl alcohol: 25.0 mg 25.0 mg
Talc: 2.5 mg
Magnesium stearate: 1.25 mg 1.25 mg
Eudragit® RS30D is available from Evonik Industries (Cas No .: 33434-24-1). Surelease® E-7-7050 is available from Colorcon Ltd.
For the preparation of the naloxone hydrochloride-containing tablets, in each case, naloxone-HCl, Povidon 30 and Lactose Flow Lac 100 were mixed in a free-fall mixer (Bohle) and spray granulated subsequently with Eudragit® RS30D respectively. Surelease® E-7-7050 in a fluidized bed granulator (GPCG3). The material was then passed over a Comill 1.4 mm sieve. Next, a granulation step with molten fatty alcohol was carried out in a forced mixer (Collette). The tablet core thus prepared has a weight of 125 mg on a dry matter basis.
Example 2
Storage stability of naloxone hydrochloride-containing tablets from Example 1:
The naloxone hydrochloride-containing tablets of Example 1 were stored at 25 ° C and 60% relative humidity for 24 months. At various times, the release ratio is examined.
With regard to the naloxone hydrochloride-containing tablet formulated with Eudragit® RS30D (Nal-5-Eud), it was determined that the release profile of the active substance naloxone hydrochloride already separated after 24 months from that immediately after the preparation of the tablet that the tablet could no longer be considered to be stock stable.
For the naloxone hydrochloride-containing tablet formulated with Surelease® E-7-7050 (Nal-5-Sure), the release also remained unchanged after 24 months of storage to the extent possible, ie. the storage stability criterion i) according to the release, regarding the release was met.
When storing the Nal-5-Eud tablet in an alu-alu blister pack (alu-alu push-through pack) or in a HDPE container with an HDPE closure and silica as a desiccant in the sealed, it was determined that the release even after 24 hours. months of storage to the greatest extent possible remained unchanged.
Example 3
Preparation of ethyl cellulose-free depot formulations containing naloxone hydrochloride (Nal-HCl) and Oxycodone hydrochloride (Oxy-HCl):
The following specification may be used to prepare tablets containing oxycodone hydrochloride / naloxone hydrochloride in the amounts of 40mg / 20mg, 20mg / 10mg, 10mg / 5mg and 5mg / 2.5mg. The amounts of excipient move within the preferred range indicated in the general section.
Step 1: Preparation of intermediate 1
Oxycodone hydrochloride, naloxone hydrochloride, microcrystalline cellulose and lactose monohydrate (lactose monohydrate only intended for formulations containing oxycodone hydrochloride / naloxone hydrochloride in the amounts of 10 mg / 5 mg and 5 mg / 2.5 mg) are mixed in a dry state in a suitable mixing device.
Dissolve povidone in water. Talc is added to the solution and slurried therein. Triacetin is suspended in the aqueous dispersion Eudragit® RS 30D. The Triace-tin / Eudragit® RS 30D slurry is added to the Povidon / talc slurry. The resulting slurry is used to granulate the dry mixture.
The resulting granulate is dried and subsequently screened. The sieved granule is mixed, from which intermediate 1 is obtained.
Step 2: Preparation of intermediate product 2
Intermediate 1 is introduced into a Hoscher mixer and briefly mixed. Stearyl alcohol is melted. The molten stearyl alcohol is added to intermediate 1. The resulting mixture is kneaded and mixed.
The resulting granulate is screened and subsequently mixed, yielding intermediate 2.
Step 3: Compression for tablet cores
Intermediate 2 is mixed with high-dispersion silica and magnesium stearate. The mixture thus obtained is pressed into tablet cores.
Step 4: Film-forming coating
Polyethylene glycol and hypromellose are dissolved in a water half. Talc, titanium dioxide and optionally one or more dyes are suspended in the other half of the water. The slurry is added to the solution. The coating of the tablet cores is done by spraying the resulting slurry.
The following table provides information on the quantitative composition of the prolonged-release tablets.
Table: Key figures for the prolonged-release tablets.
Example 4
Release profile for the tablets prepared in Example 3 containing naloxone hydrochloride and oxycodone hydrochloride: In Figures 1 and 2, for example, the release profile is shown at a pH of 6.8 (basket apparatus, stirring rate of 100 rpm) for oxycodone hydrochloride (OxyHCI), respectively. naloxone hydrochloride (NaIHCI) from the depot formulations prepared according to Example 3 containing 40 mg / 20 mg and 5 mg / 2.5 mg OxyHCI / NalHCI (test product) in comparison with the corresponding Targin® reference products containing 40 mg / 20 mg and 5 mg / 2.5 mg of OxyHCI / NalHCI.
As the figures show by way of example, the release curves for oxycodone hydrochloride and naloxone hydrochloride from the test product and from the reference product are very close to each other at a pH of 6.8. Something similar applies to the corresponding release profile at pH values of 1 and 4.5. Similarly, bioequivalence between the test products and the reference products can be established.

权利要求:
Claims (17)
[1]
A packaged medicament comprising: (a) a pharmaceutical depot formulation, wherein the pharmaceutical depot formulation comprises naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary agent for elongated release of naloxone or the pharmaceutically acceptable salt thereof; and (b) a package which is a blister pack comprising a molding film and a covering film, wherein the molding film and the covering film independently exhibit a water vapor permeability of <3.0 g / (m2-d).
[2]
The packaged medicament of claim 1, wherein the molding film is comprised of a material comprising at least one polymer or aluminum and / or the covering film is composed of a material comprising aluminum, wherein the at least one polymer is preferably selected from the group consisting of PVC, PVdC, PE, PET, PP and COC.
[3]
A packaged medicament, comprising a) a pharmaceutical depot formulation, wherein the pharmaceutical depot formulation comprises naloxone or a pharmaceutically acceptable salt thereof, oxycodone or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable auxiliary agent for the prolonged release of naloxone or the pharmaceutically acceptable salt thereof, and b) a package which is a container of closure, the container of closure comprising a desiccant.
[4]
Packaged drug according to claim 3, wherein the container and closed independently consist of a material selected from the group consisting of LDPE, HDPE, PVC, PVdC, PP, polycarbonate, COC and PET.
[5]
Packaged drug according to one of claims 3 and 4, wherein the desiccant is selected from the group consisting of sodium sulfate, silica, molecular sieve (zeolite), alumina, calcium chloride, calcium oxide, potassium carbonate, copper sulfate, magnesium sulfate, magnesium oxide, bentonite or a mixture thereof.
[6]
Packaged drug according to one of the preceding claims, wherein the pharmaceutical depot formulation is free of ethyl cellulose.
[7]
Packaged drug according to any one of the preceding claims, wherein the pharmaceutical depot formulation is matrix-based and / or surrounded by a hydrophobic film-forming coating, wherein the pharmaceutical depot formulation is preferably matrix-based and comprises at least one matrix-forming material as a pharmaceutically compatible excipient, wherein the at least one matrix forming material is preferably a polymethacrylate, especially a cationic polymethacrylate.
[8]
The packaged drug of claim 7, wherein the pharmaceutical depot formulation comprises at least one matrix forming material, at least one polymethacrylate, especially a cationic polymethacrylate, and at least one fatty alcohol, particularly stearyl alcohol, wherein the polymethacrylate and fatty alcohol are preferably present in a weight ratio of 1: 3 to 1. : 4 (fatty alcohol polymethacrylate), and / or where the weight fraction of the sum of polymethacrylate and fatty alcohol in the pharmaceutical depot formulation is 25 to 40% by weight, preferably 30 to 35% by weight, in each case based on the total weight of the depot formulation.
[9]
Packaged drug according to one of the preceding claims, wherein the depot formulation contains oxycodone hydrochloride and naloxone hydrochloride, preferably in a weight ratio of 2: 1 (oxycodone hydrochloride to naloxone hydrochloride).
[10]
Packaged drug according to one of the preceding claims, wherein the pharmaceutical depot formulation is available as (multilayer) tablet, coated pill, capsule, granule or powder, preferably as multilayer tablet.
[11]
Packaged drug according to one of the preceding claims, wherein the pharmaceutical storage formulation is not storage stable without the packaging.
[12]
Use of a pharmaceutical depot formulation as defined in claim 11 for obtaining a stock-stable drug, comprising use of packaging the depot formulation in a blister pack comprising a molding film and a covering film, wherein the molding film and the covering film exhibit a water vapor permeability independently of <10 g / (m2-d).
[13]
Use of a pharmaceutical depot formulation as defined in claim 11 for obtaining a stock stable drug, the use of which comprises packing the depot formulation in a container with the closure comprising the desiccant.
[14]
Use of a package for storage stabilization of a medicament, wherein the medicament comprises a depot formulation as defined in any one of claims 1 to 11, wherein the packaging is a blister pack comprising a molding film and a covering film, wherein molding film and covering film independently exhibit a water vapor permeability. of <10 g / (m2-d).
[15]
Use of a package for storage stabilization of a medicament, wherein the medicament comprises a pharmaceutical depot formulation as defined in any one of claims 1 to 11, wherein the package is a container of closure, wherein the container of closure comprises a desiccant.
[16]
Use of a package for limiting deallyylation of naloxone or the pharmaceutically acceptable salt thereof in a pharmaceutical depot formulation as defined in any one of claims 1 to 11 during its storage, wherein the package is a container of closure, wherein the container of closure comprises a desiccant. .
[17]
Use of a package for limiting deallylation of naloxone or its pharmaceutically acceptable salt in a pharmaceutical depot formulation as defined in any one of claims 1 to 11 during its storage, wherein the packaging is a blister pack comprising a molding film and a cover film, wherein molding film and cover film independently of one another exhibits a water vapor permeability of <10 g / (m2-d).

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同族专利:

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公开号 | 公开日

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WO2016203061A1|2016-12-22|

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DK201600098Y3|2017-02-10|

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DE202016005375U1|2016-09-30|

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AU2016101552A4|2016-10-13|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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US3773955A|1970-08-03|1973-11-20|Bristol Myers Co|Analgetic compositions|

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US3966940A|1973-11-09|1976-06-29|Bristol-Myers Company|Analgetic compositions|

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DE10215131A1|2002-04-05|2003-10-16|Euro Celtique Sa|Stable pharmaceutical preparation useful for the treatment of pain, especially severe pain, without causing side-effects comprises oxycodone and naxolone in retarded release formulation|

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DE10215067A1|2002-04-05|2003-10-16|Euro Celtique Sa|Stable pharmaceutical preparation useful for the treatment of pain, especially severe pain, without causing side-effects comprises oxycodone and naxolone in retarded release formulation|

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CA2855718A1|2011-11-17|2013-05-23|Anja Geissler|Tamper-resistant oral pharmaceutical dosage form comprising a pharmacologically active ingredient, an opioid antagonist and/or aversive agent, polyalkylene oxide and anionic polymer|

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法律状态:
2020-04-14| UBP| Utility model lapsed|Effective date: 20190902 |

优先权:

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申请号 | 申请日 | 专利标题

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DE102015011508|2015-09-03|

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DE102015014618|2015-11-12|

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CH00181/16A|CH711279B1|2015-09-03|2016-02-11|A packaged pharmaceutical composition comprising a sustained release formulation of naloxone or a pharmaceutically acceptable salt thereof and a package.|

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