Perforation of the mucosa

Abstract

The present invention relates to a kit comprising at least one microneedle system and at least one dosage form for transmucosally administering at least one active pharmaceutical ingredient, wherein the at least one dosage form for transmucosally administering at least one active pharmaceutical ingredient preferably comprises an oral membrane for use in treating a patient, the use of a microneedle system for reducing the permeability barrier of the mucosa to at least one active pharmaceutical ingredient, and a method of treating a patient, wherein the microneedle system is first applied to a mucosal site on the patient and removed again, and then an oral membrane comprising at least one matrix polymer and at least one active pharmaceutical ingredient is applied to the mucosal site after the microneedle system has been applied and removed again, or the microneedle system is applied to the mucosa simultaneously with a dosage form for transmucosally administering at least one active pharmaceutical ingredient. The present invention also relates to a biodegradable microneedle system comprising at least one active pharmaceutical ingredient and at least one biodegradable polymer.

Description

Technical Field

[0001] The present invention relates to a kit comprising at least one microneedle system and at least one dosage form for transmucosal administration of at least one pharmaceutically active ingredient, wherein at least one such dosage form for transmucosal administration comprises at least one pharmaceutically active ingredient, preferably an oral thin film, the kit for use in the treatment of a patient, the use of a microneedle system for reducing the mucosal permeation barrier to at least one pharmaceutically active ingredient, and a method of treating a patient, comprising first applying and then removing a microneedle system to a mucosal site of the patient, and then applying an oral thin film comprising at least one matrix polymer and at least one pharmaceutically active ingredient to the mucosal site to which the microneedle system has been applied and removed, or applying the microneedle system to the mucosa simultaneously with a dosage form for transmucosal administration of at least one pharmaceutically active ingredient. The present invention also relates to a biodegradable microneedle system comprising at least one pharmaceutically active ingredient and at least one biodegradable polymer.

Background Art

[0002] Pharmaceutically active ingredients can be administered via the mucosa using a suitable dosage form. For example, oral thin films are suitable for this purpose.

[0003] An oral thin film (OTF) is a thin film comprising at least one pharmaceutically active ingredient, which film is placed directly on a mucosa (mucous membrane), preferably the oral mucosa, and preferably dissolves therein. These films are in particular active ingredient-containing polymer-based thin films which deliver the active ingredient directly thereto when applied to a mucosa, in particular the oral mucosa.

[0004] This dosage form has the advantage that the active ingredient is mostly absorbed by the oral mucosa or the like, and thus, the first-pass effect that occurs in the conventional dosage form in which the active ingredient is in tablet form can be avoided. In this case, the active ingredient is dissolved, emulsified or dispersed in the membrane.

[0005] The oral mucosa in this location has good blood supply and strong blood flow, so the active ingredient is particularly rapidly absorbed here.

[0006] Therefore, the absorption pathway through the oral mucosa is characterized by a relatively rapid passage of the active ingredient or also the permeability of the active ingredient.

[0007] For example, after applying nicotine-containing OTF, an effective increase in blood pressure can be measured as a pharmacological proof already 2 minutes later.

[0008] Therefore, OTF is also preferably used for indications that require a rapid onset of action, such as pain, nausea, dizziness, seizures, cardiac arrest, but also for the regulation of hypertension or blood glucose levels.

[0009] Other suitable dosage forms include, for example, a fibrous carrier such as cotton or cellulose saturated with a solution or suspension of at least one pharmaceutical active ingredient.

[0010] In this specification, medical tampons, such as those used especially in dentistry, are suitable.

[0011] In this specification, clove oil or its main component eugenol, lavender oil or its main component linalool, methyl salicylate or an ethanol mixture of glycerin and limonene are suitable solvents.

[0012] Clove oil includes clove flower oil, clove leaf oil and clove style oil, and is generally obtained by steam distillation from various plant parts of the clove tree Syzygium aromaticum (Myrtaceae).

[0013] A suitable amount of the active ingredient present in such a fiber carrier is, for example, 50 g per 100 g of the fiber carrier.

[0014] Since the mucosa is a very hydrophilic permeation barrier (more than 90% water), the active ingredient applied thereto must be at least readily soluble in water and thus generally more hydrophilic than lipophilic. This can be achieved, for example, by administration of a pharmaceutically acceptable salt of a pharmaceutical active ingredient. For example, the hydrochlorides of the opioid bases fentanyl and buprenorphine are readily soluble in water and can be used in particular for the treatment of breakthrough pain in place of the base itself, which may be mentioned here.

[0015] However, for all covalent and lipophilic pharmaceuticals, there is no corresponding hydrophilic salt. Therefore, such pharmaceuticals, for example, riociguat for the treatment of pulmonary hypertension, or tetrahydrocannabinol (THC) for the treatment of pain, cannot be absorbed from the mucosa in sufficient amounts.

[0016] This absorption pathway is also normally blocked by active ingredients having a molecular weight above 300 g / mol or above 1000 g / mol, such as proteins like insulin, despite having sufficient water solubility.

[0017] Nevertheless, in order to provide these active ingredients in a therapeutically effective amount, it is advantageous to temporarily and reversibly reduce the mucosal permeation barrier. SUMMARY OF THE INVENTION PROBLEM TO BE SOLVED BY THE INVENTION

[0018] Therefore, an object of the present invention is to provide a method for temporarily and reversibly reducing the mucosal permeation barrier to improve the advantageous absorption of pharmaceutical active ingredients, particularly lipophilic pharmaceutical active ingredients, especially those having a logP above 3 or pharmaceutical active ingredients having a molecular weight above 300 g / mol. MEANS FOR SOLVING THE PROBLEM

[0019] This object is addressed, according to the invention, by a kit comprising at least one microneedle system and at least one dosage form for transmucosal administration of at least one pharmaceutically active ingredient, in particular an oral film comprising at least one matrix polymer and at least one pharmaceutically active ingredient.

[0020] The use of microneedles has the advantage of temporarily and reversibly reducing the mucosal permeation barrier, enabling the advantageous absorption of pharmaceutically active ingredients, in particular lipophilic pharmaceutically active ingredients, preferably those having a logP of more than 3 or a molecular weight of more than 300 g / mol.

[0021] In the following description of the invention, the term "comprising" may also mean "consisting of".

[0022] The term "microneedle" is to be understood as meaning a needle having a length of 5 to 1000 μm, preferably made of a rigid material. The ratio of length to diameter is preferably 5:1 to 1000:1.

[0023] The kit according to the invention preferably is characterized in that at least one dosage form for transmucosal administration comprises an oral film comprising a matrix polymer and at least one pharmaceutically active ingredient.

[0024] The oral film can be of a single-layer or multi-layer design.

[0025] The kit according to the invention preferably is characterized in that at least one matrix polymer comprises a water-soluble and / or water-swellable polymer.

[0026] Water-soluble and / or water-swellable polymers include chemically very different natural or synthetic polymers, the common feature of which is their solubility or degree of swelling in water or an aqueous medium.

[0027] The kit according to the present invention preferably features that at least one matrix polymer is selected from the group consisting of starch and starch derivatives, dextran, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose or propyl cellulose, cellulose derivatives such as polyacrylic acid, polyacrylate, polyvinyl pyrrolidone, polyvinyl alcohol, poly(lactide-co-glycolide), hyaluronic acid, polyethylene oxide polymer, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums. However, this group is not exhaustive.

[0028] Particularly preferred are hyaluronic acid, cellulose derivatives, alginate and / or poly(lactide-co-glycolide) because these polymers are of biological origin and are therefore pharmaceutically acceptable.

[0029] In principle, there are no restrictions on at least one pharmaceutically active ingredient contained in the oral thin film according to the present invention.

[0030] However, the kit according to the present invention preferably features that at least one pharmaceutically active ingredient contains a pharmaceutically active ingredient having a logP of 3 or more and / or a molecular weight of more than 300 g / mol.

[0031] The kit according to the present invention also preferably features that at least one pharmaceutically active ingredient has a logP of more than 2, preferably more than 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 6 or 7.

[0032] n-octanol / water partition coefficient Kow (Notations such as the octanol / water partition coefficient are also common and correct) is a dimensionless partition coefficient known to those skilled in the art, which indicates the concentration ratio of a chemical substance in a two-phase system of n-octanol and water, and is thus a measure of the hydrophobicity or hydrophilicity of the substance. The logP value is the base-10 logarithm of the n-octanol / water partition coefficient K ow and is as follows:

Equation

[0033] K ow is greater than 1 when the substance is more soluble in a fatty solvent such as n-octanol and less than 1 when it is more soluble in water. Thus, logP is positive for lipophilic substances and negative for hydrophilic substances.

[0034] Preferably, at least one pharmaceutical active ingredient has a molecular weight of more than 300 g / mol or more than 1000 g / mol, preferably more than 1500 g / mol or more than 2000 g / mol, particularly more than 2500 g / mol, more than 3000 g / mol, more than 3500 g / mol, more than 4000 g / mol, more than 4500 g / mol, or more than 5000 g / mol.

[0035] Preferably, the kit according to the present invention is characterized in that at least one pharmaceutical active ingredient has a water solubility (at 20 °C) of less than 1.0 mg / ml, preferably less than 0.5 mg / ml, 0.1 mg / ml, 0.05 mg / ml, or 0.001 mg / ml.

[0036] At least one pharmaceutical active ingredient in the kit according to the present invention is preferably selected from the group consisting of hypnotics, sedatives, antiepileptics, analeptics, psychotropic drugs, nerve blockers, neuromuscular blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, antihypertensives, pressor agents, antitussives, expectorants, analgesics, thyroid hormones, sex hormones, glucocorticoid hormones, antidiabetic agents, antitumor drugs, antibiotics, chemotherapeutic agents, anesthetics, antiparkinson drugs, anti-Alzheimer agents and / or triptans. However, this group is not exhaustive.

[0037] It is preferable that at least one pharmaceutical active ingredient contains riociguat, tetrahydrocannabinol, cannabidiol, dronabinol, thyroid hormone and / or insulin, because these active ingredients have not been able to find a good parenteral administration route so far.

[0038] It is preferable that at least one pharmaceutical active ingredient contains an active ingredient from the group of emergency medicines. These emergency medicines include adrenaline, amiodarone, antidiuretic hormone, apomorphine, atropine, hyoscine butylbromide, clonazepam, dantrolene, dexamethasone, diazepam, entrimod, etomidate, flumazenil, furosemide, glucagon, glucocorticoid, glucose, haloperidol, heparin, ketamine, levalbuterol, lidocaine, lorazepam, metoprolol, midazolam, morphine, naloxone, nitroglycerin, obidoxime chloride, orciprenaline, organic nitrates, propofol, salbutamol, terbutaline, theophylline, uterine contraction inhibitors, trimedoxime bromide and / or urapidil, and are preferably selected from the group consisting thereof.

[0039] The amount of the active ingredient in the oral thin film is determined by its type and is usually 0.01 to 70 wt%, preferably 0.1 to 50 wt%, particularly preferably 1 to 40 wt% based on the total weight of the oral thin film.

[0040] The oral film may also advantageously further comprise at least one auxiliary agent selected from the group consisting of a pigment, a flavoring agent, a sweetening agent, a taste masking agent, a surfactant, an activator, a pH adjuster, a preservative, an antioxidant and / or a plasticizer.

[0041] Preferably, each of these auxiliary agents is contained in the oral film in an amount of 0.001 to 20 wt%.

[0042] The areal density of the oral film is preferably 40 to 300 g / m 2 and particularly preferably 100 to 250 g / m 2 .

[0043] The production of such an oral film is known to those skilled in the art. Suitable production methods include dissolving or dispersing at least one pharmaceutically active ingredient and at least one matrix polymer in a suitable solvent or dispersant, respectively, and subsequently spreading and drying this solvent or dispersant to obtain the oral film.

[0044] The microneedle system, also referred to as a microneedle array, preferably includes a system having a plurality of microneedles on a carrier. The needles preferably have a length of 5 μm to 1000 μm and can be made of various materials, such as ceramic, steel, polymer or SiO2.

[0045] The kit according to the present invention is preferably characterized in that the microneedle system is a microneedle system based on glass, SiO2, steel, ceramic, starch and starch derivatives, dextran, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, sodium carboxymethyl cellulose, ethyl cellulose or propyl cellulose, polyacrylic acid, polyacrylate, polyvinyl pyrrolidone, polyvinyl alcohol, poly(lactide-co-glycolide), hyaluronic acid, polyethylene oxide polymer, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums. However, this group is not exhaustive.

[0046] A microneedle system based on hyaluronic acid, cellulose derivatives, alginate and / or poly(lactide-co-glycolide) is particularly preferred herein because these polymers are of biological origin and are therefore pharmaceutically acceptable (except for specific allergic reactions to these substances).

[0047] Suitable microneedle systems are known to those skilled in the art and are described, for example, in U.S. Patent Nos. 7,658,728, 7,785,301 or 8,414,548, the contents of which are incorporated herein in their entirety. Suitable microneedle systems are available, for example, under the trade name "AdminPatch" from "nanobioSciences" (CA, USA).

[0048] The kit according to the present invention is preferably characterized in that the microneedle system has microneedles with a length of 100 μm to 600 μm, preferably 250 μm to 350 μm, and more preferably about 300 μm.

[0049] The kit according to the present invention also preferably features that the microneedle system has 30 to 400, preferably 200 to 250 microneedles per 1 cm 2

[0050] In another embodiment, the kit according to the present invention preferably features that the microneedle system has 39 microneedles per 1 cm 2

[0051] The present invention further relates to the aforementioned kit according to the present invention for use in the treatment of a patient.

[0052] The present invention also relates to the use of the aforementioned microneedle system for reducing or decreasing the mucosal permeation barrier to at least one pharmaceutically active ingredient.

[0053] According to this use, the mucosa includes, in particular, the human oral mucosa.

[0054] At least one pharmaceutically active ingredient according to this use is understood as defined above herein.

[0055] The present invention also relates to a method for treating a patient, comprising: a) applying a microneedle system to a mucosal site of the patient; b) removing the microneedle system; and c) applying an oral thin film comprising at least one matrix polymer and at least one pharmaceutically active ingredient to the mucosal site where the microneedle system was applied in step a) and further removed in step b).

[0056] The mucosa preferably includes the human oral mucosa.

[0057] ​​​The microneedle system and at least one pharmaceutically active ingredient are understood as defined above.

[0058] The microneedle system is preferably applied to the patient's mucosa at a pressure of 1 - 5 N, preferably about 3 N.

[0059] The contact time is preferably 2 - 20 sec, particularly preferably 5 - 15 sec, especially about 10 sec.

[0060] Thereafter, the microneedle system is removed and the oral thin film is applied to the same site, preferably within 5 - 15 sec, preferably within 5 sec.

[0061] The present invention also relates to a method for treating a patient, comprising: a) applying a microneedle system to a mucosal site of the patient; b) simultaneously applying a dosage form for transmucosal administration of at least one pharmaceutically active ingredient to the side of the microneedle system that does not contact the mucosa. The present invention also relates to a method for treating a patient, comprising the above steps.

[0062] The mucosa preferably includes the human oral mucosa.

[0063] The microneedle system and at least one pharmaceutically active ingredient are understood as defined above.

[0064] The microneedle system is preferably applied to the patient's mucosa at a pressure of 1 - 5 N, preferably about 3 N.

[0065] The dosage form for transmucosal administration of at least one pharmaceutically active ingredient can be, for example, a fibrous carrier such as a dental tamponade saturated with a solution or suspension of at least one pharmaceutically active ingredient.

[0066] The present invention also relates to a biodegradable microneedle system comprising at least one pharmaceutically active ingredient and at least one biodegradable polymer.

[0067] The use of such a biodegradable microneedle system has the advantage of temporarily and reversibly reducing the mucosal permeation barrier to enable the favorable absorption of pharmaceutically active ingredients, especially lipophilic pharmaceutically active ingredients, preferably those having a logP of more than 3 or a molecular weight of more than 300 g / mol.

[0068] The term "microneedle" is understood to mean a needle having a length of 5 to 1000 μm, preferably made of a rigid material. The ratio of length to diameter is preferably 5:1 to 1000:1.

[0069] The microneedle system dissolves in the patient's oral cavity after administration, releasing the contained pharmaceutically active ingredient.

[0070] Furthermore, the biodegradable microneedle system according to the present invention is characterized in that the microneedle system has microneedles with a length of 100 μm to 500 μm, preferably 250 μm to 350 μm, and / or has 50 to 400 microneedles per 1 cm 2 preferably 200 to 250 microneedles.

[0071] It is also preferred that at least one biodegradable polymer in the biodegradable microneedle system according to the present invention is a polymer based on sugar, hyaluronic acid or polyvinylpyrrolidone.

[0072] In principle, there are no restrictions on the at least one pharmaceutically active ingredient contained in the biodegradable microneedle system according to the present invention.

[0073] However, the biodegradable microneedle system according to the present invention preferably comprises at least one pharmaceutically active ingredient having a logP of 3 or more and / or a molecular weight of more than 300 g / mol.

[0074] The biodegradable microneedle system according to the present invention also preferably comprises at least one pharmaceutically active ingredient having a logP of more than 2, preferably more than 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 6 or 7.

[0075] n-octanol / water partition coefficient K ow (Expressions such as octanol / water partition coefficient are also common and correct) is a dimensionless partition coefficient known to those skilled in the art, which indicates the concentration ratio of a chemical substance in a two-phase system of n-octanol and water, and is thus a measure of the hydrophobicity or hydrophilicity of the substance. The logP value is the base-10 logarithm of the n-octanol / water partition coefficient K ow and is as follows:

Equation

[0076] K ow is greater than 1 when the substance is more soluble in a fatty solvent such as n-octanol and less than 1 when the substance is more soluble in water. Thus, logP is positive for lipophilic substances and negative for hydrophilic substances.

[0077] At least one pharmaceutical active ingredient preferably has a molecular weight of more than 300 g / mol or more than 1000 g / mol, preferably more than 1500 g / mol or more than 2000 g / mol, particularly more than 2500 g / mol, more than 3000 g / mol, more than 3500 g / mol, more than 4000 g / mol, more than 4500 g / mol, or more than 5000 g / mol.

[0078] The biodegradable microneedle system according to the present invention is preferably characterized in that at least one pharmaceutical active ingredient has a water solubility (at 20 °C) of less than 1.0 mg / ml, preferably less than 0.5 mg / ml, 0.1 mg / ml, 0.05 mg / ml, or 0.001 mg / ml.

[0079] It is preferable that at least one pharmaceutical active ingredient does not exist in the form of a salt in the biodegradable microneedle system.

[0080] At least one pharmaceutical active ingredient in the biodegradable microneedle system according to the present invention is preferably selected from the group consisting of hypnotics, sedatives, antiepileptics, stimulants, psychotropic drugs, nerve blockers, neuromuscular blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, antihypertensives, vasopressors, antitussives, expectorants, analgesics, thyroid hormones, sex hormones, glucocorticoid hormones, antidiabetic agents, antitumor drugs, antibiotics, chemotherapeutic agents, anesthetics, antiparkinson drugs, Alzheimer's drugs and / or triptans. However, this group is not exhaustive.

[0081] It is preferable that at least one pharmaceutical active ingredient contains riociguat, tetrahydrocannabinol, cannabidiol, dronabinol, thyroid hormone, adrenaline hydrogen tartrate and / or insulin, because these active ingredients have not been able to find a good parenteral administration route so far.

[0082] At least one pharmaceutically active ingredient preferably includes an active ingredient from the group of emergency medicines. These emergency medicines include adrenaline, amiodarone, antidiuretic hormone, apomorphine, atropine, hyoscine butylbromide, clonazepam, dantrolene, dexamethasone, diazepam, entrimod, etomidate, flumazenil, furosemide, glucagon, glucocorticoid, glucose, haloperidol, heparin, ketamine, levalbuterol, lidocaine, lorazepam, metoprolol, midazolam, morphine, naloxone, nitroglycerin, obidoxime chloride, orciprenaline, organic nitrates, propofol, salbutamol, terbutaline, theophylline, uterine contraction inhibitors, trimedoxime bromide, and / or urapidil, and are preferably selected from the group consisting of them.

[0083] The amount of the active ingredient in the biodegradable micro-needle system is determined by its type and is usually 0.01 - 70 wt%, preferably 0.1 - 50 wt%, particularly preferably 1 - 40 wt% with respect to the total weight of the oral thin film.

[0084] The biodegradable micro-needle system may further advantageously include at least one auxiliary agent selected from the group consisting of dyes, flavoring agents, sweetening agents, taste masking agents, surfactants, activators, pH adjusters, preservatives, antioxidants, and / or plasticizers.

[0085] These auxiliary agents are preferably contained in the oral thin film in an amount of 0.001 - 20 wt%.

[0086] Eugenol is preferably provided as an activator in the biodegradable micro-needle system according to the present invention.

[0087] The present invention also relates to the aforementioned biodegradable micro-needle system for use as a medicine.

[0088] The present invention also relates to the above biodegradable microneedle system for use as a medicament for application to mammalian oral mucosa, particularly for application to human oral mucosa.

Brief Description of the Drawings

[0089]

Figure 1

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Figure 4

Figure 5

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Figure 9

Figure 10

Mode for Carrying Out the Invention

[0090] The present invention will be described by way of non-limiting examples below.

[0091] Example A series of the following tests on the selected active ingredient in each case was carried out at 37 °C within the range of typical in vitro permeability by a Franz diffusion cell (volume 10 mL). The used acceptor medium was completely replaced with a new one at a predetermined exchange time, and the content of the permeated active ingredient amount in these acceptor solutions was determined by HPLC.

[0092] Each of the used donor and acceptor media was selected in consideration of the solubility of the exemplified active ingredient.

[0093] In the cases of Examples 1 to 3, the used donor solution was applied directly to the mucosal surface using a pipette. The amount of the donor solution was 150 μl in any of the cases of the exemplified active ingredients 1, 2, and 3.

[0094] One of the commercially available systems made of steel is known under the trade name “AdminPatch (trademark)” from “nanobioSciences” (CA, USA) and was used as the microneedle system in Examples 1 to 4 and 10.

[0095] The contact pressure was monitored by an upper pan balance and was 3 N with the pressure applied by the thumb. The pressurization time was 10 sec.

[0096] The length of the microneedles in Examples 1 to 4 and 10 was 600 μm in any case. A total of 187 microneedles were applied to an area of 0.785 cm 2 (the microneedle density was 238 per cm 2 ).

[0097] In Example 4, the donor solution was injected onto or into the dental tamponde (length and diameter are each 1 cm) used (900 μl). The microneedle system was fixed under the tamponde, and then applied vertically to the mucosal surface by the head of the Franz cell and fixed in a prescribed position with an appropriate stopper at an appropriate pressure.

[0098] In Examples 5 to 9, the biodegradable micron needle system added with the active ingredient was tested by the Franz diffusion cell as described above.

[0099] In Example 10, the oral thin film containing the active ingredient was applied to the pretreated mucosal surface in the same manner as in Examples 1 to 3 using the "AdminPatch (trademark)" micron needle system (needle length 600 μm).

[0100] The results of the permeation tests using various active ingredients are shown in FIGS. 1 to 10.

Example

[0101] Permeation test using riociguat As the acceptor medium, phosphate buffer (pH 5.5) was used, and 2 wt% of Tween (registered trademark) 20 was added as an organic solvent to maintain the "sink" condition (sink means that the solubility of the active ingredient at time t in the acceptor medium is at most 30% of its saturation solubility in this acceptor medium).

[0102] A saturated riociguat solution in clove oil (Primavera (registered trademark), Oy-Mittelberg, Germany, an organic essential oil of clove buds) was used as the donor solution.

[0103] Skin with a layer thickness of 400 μm obtained from porcine esophagus was used as the skin model.

[0104] The results of the permeation test are shown in FIG. 1.

Example

[0105] Permeation test using human insulin A 0.025 molar concentration of HEPES buffer (pH 7.4) was used as the acceptor medium.

[0106] A saturated human insulin solution in natural human saliva was used as the donor solution.

[0107] Skin with a layer thickness of 400 μm obtained from porcine esophagus was used as a skin model.

[0108] The results of the permeation test are shown in Fig. 2.

Example

[0109] Permeation test using tetrahydrocannabinol (THC) The acceptor medium used was phosphate buffer (pH 5.5), to which 2 wt% of Tween® 20 was added as an organic solvent to maintain "sink" conditions.

[0110] A saturated tetrahydrocannabinol solution in clove oil (Primavera®, Oy-Mittelberg, Germany, an organic essential oil of clove buds) was used as the donor solution.

[0111] Skin with a layer thickness of 400 μm obtained from porcine esophagus was used as a skin model.

[0112] The results of the permeation test are shown in Fig. 3.

Example

[0113] Permeation test using cannabidiol (CBD) The acceptor medium used was phosphate buffer (pH 5.5), to which 2 wt% of Tween® 20 used as an organic solvent to maintain "sink" conditions was added.

[0114] A saturated tetrahydrocannabinol solution in clove oil (Primavera®, Oy-Mittelberg, Germany, an organic essential oil of clove buds) was used as the donor solution.

[0115] Skin with a layer thickness of 400 μm obtained from porcine esophagus was used as a skin model.

[0116] The results of the permeation test are shown in Figure 4.

Example

[0117] Permeation test using sumatriptan succinate Phosphate buffer (pH 7.4) without further additives was used as the acceptor medium; sumatriptan succinate as a water-soluble salt is very soluble in this acceptor.

[0118] The donor system was a polyvinylpyrrolidone-based micro-needle system, which had sumatriptan succinate added and dissolved when contacted with water at a temperature of 32 °C or higher.

[0119] In the production, sumatriptan succinate, polyvinylpyrrolidone, polysorbate 80 and glycerin were dissolved in water at a ratio of 5:20:1:1:73 (in each case unit wt%). The completed solution was poured into a silicone negative needle mold, and its surface was coated with a thin platinum layer by vacuum metallization. Then, the negative mold was dried overnight at room temperature. The dried micro-needle system was carefully extruded from the mold after the drying process and stored avoiding moisture until later use. The active ingredient content was 4.25 mg of sumatriptan succinate per 0.785 cm 2 or 5.41 mg / cm 2 of it.

[0120] The length of the micro-needles of the used micro-needle system was 500 μm. A total of 600 micro-needles were applied to an area of 0.785 cm 2 (the micro-needle density was 764 per 1 cm 2 ).

[0121] Skin with a layer thickness of 400 μm taken from a porcine esophagus was used as a skin model.

[0122] The microneedle system was retained on the mucosa throughout the permeation period and further filled with lead balls to simulate the in vivo contact pressure in the oral cavity (e.g., between the mandible and the oral mucosa). To protect the dissolving microneedle system, a separation film based on silicone-treated PET (polyethylene terephthalate) was also introduced between and in front of the lead balls.

[0123] The results of the permeation test are shown in Figure 5.

Example

[0124] Permeation test using adrenaline hydrogen tartrate Phosphate buffer (pH 6.0) with 0.1 wt% L-ascorbic acid was used as the acceptor medium; adrenaline hydrogen tartrate is very soluble in this acceptor.

[0125] The biodegradable microneedle system was manufactured and applied in the same manner as in Example 5 using adrenaline hydrogen tartrate as the pharmaceutically active ingredient.

[0126] The results of the permeation test are shown in Figure 6.

Example

[0127] Permeation test using salbutamol sulfate Phosphate buffer (pH 7.4) without further additives was used as the acceptor medium; salbutamol sulfate is very soluble in this acceptor.

[0128] The biodegradable microneedle system was manufactured and applied in the same manner as in Example 5 using salbutamol sulfate as the pharmaceutically active ingredient.

[0129] The results of the permeation test are shown in Figure 7.

Example

[0130] Permeation test using apomorphine hydrochloride A phosphate buffer (pH 6.8) containing 0.1 wt% L-ascorbic acid was used as the acceptor medium; apomorphine hydrochloride is very soluble in this acceptor.

[0131] A biodegradable micro-needle system was prepared in the same manner as in Example 5 using apomorphine hydrochloride as the pharmaceutically active ingredient.

[0132] The results of the permeation test are shown in Figure 8.

Example

[0133] Permeation test using sumatriptan base A phosphate buffer (pH 6.0) containing 2 wt% Tween 20 was used as the acceptor medium; sumatriptan base is very soluble in this acceptor.

[0134] A biodegradable micro-needle system was prepared and applied in the same manner as in Example 5 using sumatriptan base as the pharmaceutically active ingredient.

[0135] The results of the permeation test are shown in Figure 9.

Example

[0136] An oral thin film was prepared as follows: 1) The active ingredient (25 g) was weighed and placed in water (50 g), and suspended in water while stirring (1200 rpm for 1 h), 2) Further constituent components hydroxypropyl methylcellulose 60 g, glycerin 15 g, and sodium saccharin 3 g were continuously added little by little while stirring, 3) The batch was stored in the refrigerator overnight, 4) The batch was homogenized at 1350 rpm for 5 min using an UltraTurrax device, 5) The batch was stored in the refrigerator overnight again, 6) A thin film (layer thickness 800 μm) was taken out onto the side of the 1200-μm thick laminated paper that had not been silicon-treated, using a dispensing doctor blade (Erichsen® Handheld Doctor Blade). 7) The taken-out film was dried at room temperature for 10 min and then at 70 °C for 20 min in a circulating air drying oven. 8) Circular blanks (diameter 25 cm) were punched out from the film and enclosed in pouches sealed on all four sides.

[0137] The oral thin film had the following composition (unit: wt%): Ulipristal acetate as the active ingredient: 25% Polymer consisting of hydroxypropyl methylcellulose: 60% Glycerin: 12% Sodium saccharin: 3%.

[0138] Phosphate buffer (pH 7.4) with 2 wt% Tween 20 was used as the acceptor medium; ulipristal acetate is very soluble in this acceptor.

[0139] The treatment of the mucosal surface was carried out for 10 sec with a contact pressure of 3 N by pressing the thumb monitored by an upper-pan balance, using a steel "AdminPatch®" micro-needle system (needle length 600 μm) from "nanobioSciences" (CA, USA).

[0140] Immediately afterwards, preferably 100 μl of Glandosane® was added simultaneously to initiate the dissolution of the oral thin film, and the oral thin film was applied.

[0141] Oral films must always start the dissolution process as so-called semi-solid substances. The agent used here to initiate dissolution should preferably mimic a naturally produced saliva, which dissolves the oral film or at least initiates dissolution in vivo. In this case, Glandosane® was used to improve solubility. Glandosane® (artificial saliva) is a spray applied intraorally for xerostomia and oral care in intensive care units.

[0142] The results of the permeation test are shown in Figure 10.

Claims

Claim 1 At least one microneedle system, and At least one dosage form for transmucosal administration of at least one pharmaceutically active ingredient A kit comprising: The at least one dosage form comprises an oral thin film comprising at least one matrix polymer and at least one pharmaceutically active ingredient, and the at least one matrix polymer comprises a water-soluble and / or water-swellable polymer, said kit. Claim 2 The water-soluble and / or water-swellable polymer is selected from the group consisting of starch and starch derivatives, dextran, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose and propyl cellulose cellulose derivatives, polyacrylic acid, polyacrylate, polyvinyl pyrrolidone, polyvinyl alcohol, poly(lactide-co-glycolide), hyaluronic acid, polyethylene oxide polymer, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums, the kit according to claim 1. Claim 3 The at least one pharmaceutically active ingredient comprises a pharmaceutically active ingredient having a logP of 3 or more, the kit according to claim 1 or 2. Claim 4 The at least one pharmaceutically active ingredient comprises a pharmaceutically active ingredient having a molecular weight of more than 300 g / mol, the kit according to any one of claims 1 to 3. Claim 5 The at least one pharmaceutically active ingredient is selected from the group consisting of hypnotics, sedatives, antiepileptics, analeptics, psychotropic drugs, nerve blockers, neuromuscular blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, antihypertensives, pressor agents, antitussives, expectorants, analgesics, thyroid hormones, sex hormones Lumones, glucocorticoid hormones, antidiabetic agents, antitumor drugs, antibiotics, chemotherapeutic agents, anesthetics, anti-Parkinson drugs, anti-Alzheimer agents and / or triptans, the kit according to any one of claims 1 to 4. Claim 6 The microneedle system is made of cellulose derivatives selected from the group consisting of glass, SiO 2 , steel, ceramics, starch and starch derivatives, dextran, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose and propyl cellulose, polyacrylic acid, polyacrylate, polyvinyl pyrrolidone, polyvinyl alcohol, poly(lactide-co-glycolide), hyaluronic acid, polyethylene oxide polymer, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums, and is a microneedle system based on the above, and the kit according to any one of claims 1 to 5 is characterized in that. Claim 7 The microneedle system has microneedles with a length of 100 μm to 600 μm, preferably 250 μm to 350 μm, and / or has 50 to 400, preferably 200 to 250, microneedles per 1 cm 2 The kit according to any one of claims 1 to 6, characterized by having microneedles with a length of 100 μm to 600 μm, preferably 250 μm to 350 μm, and / or having 50 to 400, preferably 200 to 250, microneedles per 1 cm Claim 8 The kit according to any one of claims 1 to 7, characterized in that at least one pharmaceutically active ingredient comprises riociguat, insulin, tetrahydrocannabinol, cannabidiol, sumatriptan, adrenaline, apomorphine, and / or ulipristal acetate.

9. The kit according to any one of claims 1 to 8 for use in the treatment of a patient.

10. Use of a microneedle system for manufacturing the kit according to claim 1, which reduces the mucosal permeation barrier to at least one pharmaceutically active ingredient.

11. A kit for use in a method of treating a patient, the method comprising: a) applying a microneedle system to the mucosal site of the patient; b) removing the microneedle system; and c) applying an oral thin film comprising at least one matrix polymer and at least one pharmaceutically active ingredient, wherein the at least one matrix polymer comprises a water-soluble and / or water-swellable polymer, to the mucosal site where the microneedle system was applied in step a) and removed again in step b). comprising the kit comprising the microneedle system and the oral thin film.

12. A kit for use in a method of treating a patient, the method comprising: a) applying a microneedle system to the mucosal site of the patient; b) simultaneously applying an oral thin film comprising at least one matrix polymer and at least one pharmaceutically active ingredient, wherein the at least one matrix polymer comprises a water-soluble and / or water-swellable polymer, to the side of the microneedle system that does not contact the mucosa. comprising the kit comprising the microneedle system and the oral thin film.

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