WO2022207257A1 - Oral thin film - Google Patents
Oral thin film Download PDFInfo
- Publication number
- WO2022207257A1 WO2022207257A1 PCT/EP2022/055928 EP2022055928W WO2022207257A1 WO 2022207257 A1 WO2022207257 A1 WO 2022207257A1 EP 2022055928 W EP2022055928 W EP 2022055928W WO 2022207257 A1 WO2022207257 A1 WO 2022207257A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- thin film
- oral thin
- carboxyl groups
- free carboxyl
- polymer
- Prior art date
Links
- 239000010409 thin film Substances 0.000 title claims abstract description 70
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 45
- 229920000642 polymer Polymers 0.000 claims abstract description 44
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229960003299 ketamine Drugs 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 229920003169 water-soluble polymer Polymers 0.000 claims description 9
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 8
- 229920002678 cellulose Polymers 0.000 claims description 6
- 239000001913 cellulose Substances 0.000 claims description 6
- -1 hydroxypropylethyl Chemical group 0.000 claims description 6
- YQEZLKZALYSWHR-ZDUSSCGKSA-N (S)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@@]1(NC)CCCCC1=O YQEZLKZALYSWHR-ZDUSSCGKSA-N 0.000 claims description 5
- 229920001577 copolymer Polymers 0.000 claims description 5
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 3
- 230000036407 pain Effects 0.000 claims description 3
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- OMDQUFIYNPYJFM-XKDAHURESA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[[(2r,3s,4r,5s,6r)-4,5,6-trihydroxy-3-[(2s,3s,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]methoxy]oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@H](O)[C@H](O)O1 OMDQUFIYNPYJFM-XKDAHURESA-N 0.000 claims description 2
- SATHPVQTSSUFFW-UHFFFAOYSA-N 4-[6-[(3,5-dihydroxy-4-methoxyoxan-2-yl)oxymethyl]-3,5-dihydroxy-4-methoxyoxan-2-yl]oxy-2-(hydroxymethyl)-6-methyloxane-3,5-diol Chemical compound OC1C(OC)C(O)COC1OCC1C(O)C(OC)C(O)C(OC2C(C(CO)OC(C)C2O)O)O1 SATHPVQTSSUFFW-UHFFFAOYSA-N 0.000 claims description 2
- 229920001817 Agar Polymers 0.000 claims description 2
- 229920000936 Agarose Polymers 0.000 claims description 2
- 239000001904 Arabinogalactan Substances 0.000 claims description 2
- 229920000189 Arabinogalactan Polymers 0.000 claims description 2
- 241000416162 Astragalus gummifer Species 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 102000008186 Collagen Human genes 0.000 claims description 2
- 108010035532 Collagen Proteins 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 229920000926 Galactomannan Polymers 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 239000004373 Pullulan Substances 0.000 claims description 2
- 229920001218 Pullulan Polymers 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 229920001615 Tragacanth Polymers 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 239000008272 agar Substances 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 235000019312 arabinogalactan Nutrition 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 235000010418 carrageenan Nutrition 0.000 claims description 2
- 229920001525 carrageenan Polymers 0.000 claims description 2
- 239000000679 carrageenan Substances 0.000 claims description 2
- 229940113118 carrageenan Drugs 0.000 claims description 2
- 229940045110 chitosan Drugs 0.000 claims description 2
- 229920001436 collagen Polymers 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000003995 emulsifying agent Substances 0.000 claims description 2
- 239000003623 enhancer Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 235000003599 food sweetener Nutrition 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 239000003906 humectant Substances 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 2
- 235000019426 modified starch Nutrition 0.000 claims description 2
- 229920001206 natural gum Polymers 0.000 claims description 2
- 235000010987 pectin Nutrition 0.000 claims description 2
- 229920001277 pectin Polymers 0.000 claims description 2
- 239000001814 pectin Substances 0.000 claims description 2
- 239000004014 plasticizer Substances 0.000 claims description 2
- 229920002401 polyacrylamide Polymers 0.000 claims description 2
- 229920000058 polyacrylate Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- 239000003755 preservative agent Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 235000019423 pullulan Nutrition 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 239000003765 sweetening agent Substances 0.000 claims description 2
- 239000006068 taste-masking agent Substances 0.000 claims description 2
- 235000010487 tragacanth Nutrition 0.000 claims description 2
- 239000000196 tragacanth Substances 0.000 claims description 2
- 229940116362 tragacanth Drugs 0.000 claims description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 description 14
- 239000002585 base Substances 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000010408 film Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 210000002200 mouth mucosa Anatomy 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- YQEZLKZALYSWHR-CYBMUJFWSA-N (R)-(+)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@]1(NC)CCCCC1=O YQEZLKZALYSWHR-CYBMUJFWSA-N 0.000 description 1
- ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 229920003136 Eudragit® L polymer Polymers 0.000 description 1
- 229920003083 Kollidon® VA64 Polymers 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- VCMGMSHEPQENPE-ZOWNYOTGSA-N esketamine hydrochloride Chemical compound [Cl-].C=1C=CC=C(Cl)C=1[C@@]1([NH2+]C)CCCCC1=O VCMGMSHEPQENPE-ZOWNYOTGSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000002694 regional anesthesia Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
Definitions
- the present invention relates to an oral thin film for the administration of ketamine, a method for its production, and the use of such an oral thin film as a medicament, in particular in the treatment of pain and/or depression.
- Oral thin films are thin films containing at least one pharmaceutically active ingredient that are placed directly in the oral cavity or applied to the oral mucosa and dissolve or swell there and thereby release the active ingredient.
- These are, in particular, thin polymer-based films containing active substance which, when applied to a mucous membrane, in particular the oral mucosa, can release the active substance directly into the latter.
- the very good blood circulation in the oral mucosa ensures that the active substance enters the bloodstream quickly.
- This delivery system has the advantage that the active ingredient is largely absorbed through the mucous membrane, thus avoiding the "first-pass metabolism” that occurs with the conventional dosage form of an active ingredient in tablet form.
- the active ingredient can be dissolved, emulsified or dispersed in the film will.
- Oral thin films known from the prior art for administering ketamine based on water-soluble polymers have the disadvantage that they disintegrate relatively quickly on contact with aqueous media. Thus the Active ingredient released very quickly, which can be disadvantageous depending on the treatment regimen. In the case of the known systems, this disintegration time can only be varied by laboriously varying the entire formulation.
- the object of the present invention is to eliminate the aforementioned disadvantages of the prior art.
- the object of the present invention is to provide an oral thin film for the administration of ketamine with a relatively long, preferably easily variable, disintegration time, wherein ketamine is chemically and physically stably dissolved in the oral thin film.
- the oral thin film should be simple and inexpensive to produce.
- an oral thin film according to claim 1 comprising ketamine or a pharmaceutically acceptable salt thereof, at least one polymer comprising free carboxyl groups, wherein 10 to 100%, more preferably 15 to 100%, of the free carboxyl groups of the at least one Polymer comprising free carboxyl groups, neutralized as a salt, includes.
- the polymer is preferably insoluble. If approximately 10% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized, the polymer preferably has a pH of approximately 4 (in aqueous solution at 20° C.) and is therefore very slowly soluble. If approximately 15% to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized, the polymer preferably has a pH of approximately 4.5 to 7 (in aqueous solution at 20° C.).
- the values given for the degree of neutralization of the free carboxyl groups relate to the sum of all carboxyl groups present.
- the at least one polymer comprising free carboxyl groups is preferably a sparingly soluble, very sparingly soluble or practically insoluble polymer according to the table below.
- Solubility in water at 15°C to 25°C It has been shown that the solubility of polymers containing free carboxyl groups in water can be varied by adding at least one base. Applied to the oral thin film, this means that the disintegration time of the oral thin film in the patient's mouth can also be easily varied by the presence of at least one base in the oral thin film.
- the oral thin film according to the invention is further characterized in that the free carboxyl groups of the at least one polymer comprising free carboxyl groups have been neutralized by adding at least one base, preferably NaOH.
- alkali metal or alkaline earth metal hydroxides are also suitable as bases, for example KOH.
- the amount of the at least one base is preferably from 1 to 15% by weight, in particular from 0.7 to 3% by weight, based on the weight of the at least one polymer which comprises free carboxyl groups.
- the amount of the at least one base added is preferably such that the equivalence ratio of the base to the free carboxyl groups of the at least one polymer comprising free carboxyl groups is 1:10 to 2:1, preferably 1:10 to 1:1.
- the amount of base used also depends on the molecular weight of the base and on its solubility.
- the at least one polymer which comprises free carboxyl groups, preferably comprises a polymer based on (meth)acrylic acid and/or based on a copolymer of (meth)acrylic acid and (meth)acrylic acid esters.
- the at least one polymer comprising free carboxyl groups comprises a copolymer of (meth)acrylic acid and (meth)acrylic acid esters, very particularly preferably a (meth)acrylic acid/ethyl acrylate copolymer.
- Suitable polymers are available, for example, under the trade names Eudragit L (from Evonik) or Kollicoat MAE (from BASF). These polymers have the advantage that they are almost insoluble in water and this solubility can be easily varied by adding at least one base. Furthermore, these polymers are well compatible with the active ingredient ketamine.
- the oral thin film of the present invention preferably further comprises at least one water-soluble polymer.
- Water-soluble polymers include chemically very different, natural or synthetic polymers whose common feature is their solubility in water or aqueous media. The prerequisite is that these polymers have a sufficient number of hydrophilic groups for water solubility and are not crosslinked.
- the hydrophilic groups can be non-ionic, anionic, cationic and/or zwitterionic.
- Water-soluble polymers preferably have a solubility in water according to the table above of at least "soluble".
- the at least one water-soluble polymer is preferably selected from starch and starch derivatives, dextrans, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates, polyvinylpyrrolidones, vinylpyrrolidone/vinyl acetate copolymers, polyvinyl alcohols, polyethylene oxide polymers , polyacrylamides, polyethylene glycols, gelatin, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums.
- cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,
- the addition of such a water-soluble polymer has the advantage that the compatibility between the film and the drug can be improved (e.g. also to stabilize a solid solution). Furthermore, the additional polymer can serve as a filler, for example to achieve a certain weight/thickness of the oral thin film.
- the oral thin film according to the invention is preferably characterized in that the at least one water-soluble polymer is present in an amount of 5 to 40% by weight, preferably 8 to 30% by weight, particularly preferably 10 to 25% by weight % by weight based on the total weight of the oral thin film is present in the oral thin film.
- Ketamine and/or a pharmaceutically acceptable salt thereof, preferably ketamine-HCl is present in the oral thin film of the present invention.
- (S)-ketamine or a pharmaceutically acceptable salt thereof, in particular (S)-ketamine-HCl is particularly preferred as the sole stereoisomer of ketamine, since the analgesic and anesthetic potency of (S)-ketamine is approximately three-fold higher than that of (R) form.
- the oral thin film of the present invention is further preferably characterized in that the ketamine is present in an amount of 1 to 50% by weight, preferably 10 to 40% by weight, more preferably 25 to 35% by weight based on the total weight of the oral thin film in which oral thin film is present.
- the oral thin film according to the invention is preferably characterized in that the at least one polymer comprising free carboxyl groups is present in an amount of 1 to 50% by weight, preferably 10 to 40% by weight, particularly preferably 25 to 35% by weight % based on the total weight of the oral thin film is present in the oral thin film.
- the oral thin film according to the invention is preferably characterized in that the oral thin film contains at least one excipient selected from the group comprising dyes, plasticizers (such as glycerin), flavorings, sweeteners, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and/or or antioxidants.
- excipients selected from the group comprising dyes, plasticizers (such as glycerin), flavorings, sweeteners, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and/or or antioxidants.
- Each of these excipients is preferably contained in the oral thin film in an amount of about 0.1 to 10% by weight based on the total weight of the oral thin film.
- the oral thin film of the present invention preferably has an area of from about 0.5 cm 2 to about 10 cm 2 , more preferably from about 2 cm 2 to about 8 cm 2 .
- the oral thin film of the present invention is preferably characterized in that the basis weight of the oral thin film is about 50 to 300 g/m 2 , preferably about 100 to 200 g/m 2 .
- This preferably corresponds to a layer thickness of preferably about 20 ⁇ m to about 500 ⁇ m, particularly preferably from about 50 ⁇ m to about 300 ⁇ m.
- the oral thin film of the present invention preferably dissolves in the oral cavity in a period greater than about 10 minutes, more preferably in a period greater than about 20 minutes, more preferably in a period of 20 to 40 minutes.
- the present invention further relates to a method for producing the oral thin film of the present invention.
- the method comprises the steps a) preparing a solution, preferably based on a mixture comprising water and/or at least one organic solvent, such as ethanol, comprising ketamine, at least one polymer comprising free carboxyl groups, with 10 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups, present in neutralized form as a salt, and, if present, the other ingredients; b) spreading out and drying the solution obtained according to step a), so that the dried solution preferably has a basis weight of about 50 to about 300 g/m 2 .
- step a) is designed as follows. a) preparing a solution, preferably based on a mixture comprising water and/or at least one organic solvent such as ethanol, comprising ketamine, at least one base, preferably NaOH, and the at least one polymer comprising free carboxyl groups, and, if present, the other ingredients.
- a) preparing a solution, preferably based on a mixture comprising water and/or at least one organic solvent such as ethanol, comprising ketamine, at least one base, preferably NaOH, and the at least one polymer comprising free carboxyl groups, and, if present, the other ingredients.
- the at least one polymer which comprises free carboxyl groups, is partially neutralized directly in the solution by adding at least one base.
- All preferred embodiments and definitions for the oral thin film according to the invention apply analogously to the method according to the invention.
- the present invention further relates to an oral thin film obtainable by the method described above.
- the present invention relates to an oral thin film as described above or obtainable by the method described above as a medicament.
- the present invention also relates to an oral thin film as described above or obtainable by the method described above as a medicament for use in the treatment of pain and/or depression, in particular for reducing the risk of suicide and/or for use as a general anaesthetic, preferably for induction and administration of general anesthesia or as an adjunct to regional anesthesia and/or as an analgesic.
- Figure 1 shows the permeation data of the formulations according to Table 1.
- Figure 2 shows the in vitro release data of the formulations according to Table 1.
- Kollicoat MAE (meth)acrylic acid/ethyl acrylate copolymer from BASF
- the solvent is introduced and the ingredients according to Table 1 are dissolved one after the other.
- the mass is now left to rest until it is bubble-free.
- the mass is applied to a siliconized liner and the resulting film is dried.
- the permeation of the active ingredient was determined according to the following procedure.
- Esophageal mucosa (domestic pig) with a layer thickness of 400 ⁇ m was used as a skin model.
- Phosphate buffer pH 7.4 was used as the acceptor medium.
- the comparison measurement was carried out against the quick-release foam formulation (140Kea0002) used, which has a composition according to the table below.
- Figure 1 shows that in the formulations 140Kea0041 (1% NaOH), 140Kea0043 (2% NaOH), 140Kea0044 (2.8% NaOH) the permeation slows down significantly with increasing NaOH content until it is in the formulation 140Kea0047 (9th % NaOH) stagnates.
- the disintegration time was tested in a further experiment and confirmed the results shown in the permeation.
- the formulation 140Kea0041 1% NaOH was shown to have the highest disintegration time, which correlates with the slowest release.
- the disintegration time of the oral thin films was measured using the USP Method ⁇ 701> Disintegration, from 2016.
- the in vitro release was determined as follows:
- S-ketamine is released from the oral thin film (OTF) and determined.
- the drug is released in phosphate buffer pH 6.8 USP and then determined by a gradient reverse phase HPLC method. The quantification was carried out against an external standard.
- Dissolution is performed with Dissolution Apparatus 2 - (Paddle over sinker) according to USP ⁇ 711>.
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Abstract
The invention relates to an oral thin film, comprising ketamine or a pharmaceutically acceptable salt thereof, and at least one polymer including free carboxyl groups, wherein 10 to 100% of the free carboxyl groups of the at least one polymer including free carboxyl groups are present in neutralized form, as a salt. The invention further relates to a method for the production of said oral thin film and to its use as a drug.
Description
Oraler Dünnfilm Oral Thin Film
Die vorliegende Erfindung betrifft einen oralen Dünnfilm zur Verabreichung von Ketamin, ein Verfahren zu dessen Herstellung, sowie die Verwendung eines solchen oralen Dünnfilms als Arzneimittel, insbesondere in der Behandlung von Schmerzen und/oder Depressionen. The present invention relates to an oral thin film for the administration of ketamine, a method for its production, and the use of such an oral thin film as a medicament, in particular in the treatment of pain and/or depression.
Orale Dünnfilme sind dünne, mindestens einen pharmazeutisch aktiven Wirkstoff enthaltende Filme, die direkt in den Mundraum gelegt oder an die Mundschleimhaut angelegt werden und sich dort auflösen bzw. aufquellen und dabei den Wirkstoff abgeben. Dabei handelt es sich insbesondere um dünne wirkstoffhaltige Filme auf Polymerbasis, die, wenn sie auf eine Schleimhaut, insbesondere die Mundschleimhaut, aufgebracht werden, den Wirkstoff direkt in diese abgeben können. Die sehr gute Durchblutung der Mundschleimhaut sorgt für einen schnellen Übergang des Wirkstoffs in den Blutkreislauf. Dieses Darreichungssystem hat den Vorteil, dass der Wirkstoff größtenteils durch die Schleimhaut resorbiert wird und damit der „First-Pass Metabolismus", der bei der konventionellen Darreichungsform eines Wirkstoffs in Tablettenform auftritt, vermieden wird. Der Wirkstoff kann in dem Film gelöst, emulgiert oder dispergiert werden. Oral thin films are thin films containing at least one pharmaceutically active ingredient that are placed directly in the oral cavity or applied to the oral mucosa and dissolve or swell there and thereby release the active ingredient. These are, in particular, thin polymer-based films containing active substance which, when applied to a mucous membrane, in particular the oral mucosa, can release the active substance directly into the latter. The very good blood circulation in the oral mucosa ensures that the active substance enters the bloodstream quickly. This delivery system has the advantage that the active ingredient is largely absorbed through the mucous membrane, thus avoiding the "first-pass metabolism" that occurs with the conventional dosage form of an active ingredient in tablet form. The active ingredient can be dissolved, emulsified or dispersed in the film will.
Aus dem Stand der Technik bekannte orale Dünnfilme zur Verabreichung von Ketamin auf Basis von wasserlöslichen Polymeren haben den Nachteil, dass diese bei Kontakt mit wässrigen Medien relativ schnell zerfallen. Somit wird der
Wirkstoff sehr schnell freigesetzt, was je nach Behandlungsschema unvorteilhaft sein kann. Eine Variation dieser Zerfallszeit ist bei den bekannten Systemen nur durch eine aufwändige Variierung der gesamten Formulierung möglich. Oral thin films known from the prior art for administering ketamine based on water-soluble polymers have the disadvantage that they disintegrate relatively quickly on contact with aqueous media. Thus the Active ingredient released very quickly, which can be disadvantageous depending on the treatment regimen. In the case of the known systems, this disintegration time can only be varied by laboriously varying the entire formulation.
Die Aufgabe der vorliegenden Erfindung besteht darin, vorstehend genannte Nachteile des Standes der Technik zu beheben. Insbesondere besteht die Aufgabe der vorliegenden Erfindung darin, einen oralen Dünnfilm zur Verabreichung von Ketamin mit einer relativ langen, vorzugsweise einfach zu variierenden Zerfallszeit, bereitzustellen, wobei Ketamin, chemisch und physikalisch stabil in dem oralen Dünnfilm gelöst, vorliegt. Zudem soll der orale Dünnfilm einfach und kostengünstig herzustellen sein. The object of the present invention is to eliminate the aforementioned disadvantages of the prior art. In particular, the object of the present invention is to provide an oral thin film for the administration of ketamine with a relatively long, preferably easily variable, disintegration time, wherein ketamine is chemically and physically stably dissolved in the oral thin film. In addition, the oral thin film should be simple and inexpensive to produce.
Obige Aufgabe wird durch einen oralen Dünnfilm nach Anspruch 1 gelöst, der Ketamin oder ein pharmazeutisch akzeptables Salz davon, mindestens ein Polymer, das freie Carboxylgruppen umfasst, wobei 10 bis 100%, besonders bevorzugt von 15 bis 100%, der freien Carboxylgruppen des mindestens einen Polymers, das freie Carboxylgruppen umfasst, neutralisiert als Salz vorliegen, umfasst. The above object is achieved by an oral thin film according to claim 1 comprising ketamine or a pharmaceutically acceptable salt thereof, at least one polymer comprising free carboxyl groups, wherein 10 to 100%, more preferably 15 to 100%, of the free carboxyl groups of the at least one Polymer comprising free carboxyl groups, neutralized as a salt, includes.
Vorzugsweise liegen 15 bis 100% oder 20 bis 100% oder 25 bis 100% oder 30 bis 100% oder 35 bis 100% oder 40 bis 100% oder 45 bis 100% oder 50 bis 100% oder 60 bis 100% oder 70 bis 100% oder 80 bis 100% oder 90 bis 100% der freien Carboxylgruppen des mindestens einen Polymers, das freie Carboxylgruppen umfasst, neutralisiert als Salz vor. Preferably there is 15 to 100% or 20 to 100% or 25 to 100% or 30 to 100% or 35 to 100% or 40 to 100% or 45 to 100% or 50 to 100% or 60 to 100% or 70 to 100 % or 80 to 100% or 90 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized as a salt.
Vorzugsweise liegen 10 bis 100% oder 15 bis 100% oder 20 bis 95% oder 25 bis 90% oder 30 bis 85% oder 35 bis 80% oder 40 bis 75% oder 45 bis 70% oder 50 bis 65% oder 55 bis 60% der freien Carboxylgruppen des mindestens einen Polymers, das freie Carboxylgruppen umfasst, neutralisiert als Salz vor. Preferably there is 10 to 100% or 15 to 100% or 20 to 95% or 25 to 90% or 30 to 85% or 35 to 80% or 40 to 75% or 45 to 70% or 50 to 65% or 55 to 60 % of the free carboxyl groups of the at least one polymer comprising free carboxyl groups, neutralized as a salt.
Sind 0% der freien Carboxylgruppen des mindestens einen Polymers, das freie Carboxylgruppen umfasst neutralisiert, so ist das Polymer vorzugsweise unlöslich. Sind etwa 10% der freien Carboxylgruppen des mindestens einen Polymers, das freie Carboxylgruppen umfasst neutralisiert, so weist das Polymer vorzugsweise einen pH von etwa 4 (in wässriger Lösung bei 20°C) auf und ist damit sehr langsam löslich.
Sind etwa 15% bis 100% der freien Carboxylgruppen des mindestens einen Polymers, das freie Carboxylgruppen umfasst neutralisiert, so weist das Polymer vorzugsweise einen pH von etwa 4,5 bis 7 (in wässriger Lösung bei 20°C) auf. If 0% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized, the polymer is preferably insoluble. If approximately 10% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized, the polymer preferably has a pH of approximately 4 (in aqueous solution at 20° C.) and is therefore very slowly soluble. If approximately 15% to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized, the polymer preferably has a pH of approximately 4.5 to 7 (in aqueous solution at 20° C.).
Ist mehr als ein Polymer, das freie Carboxylgruppen umfasst vorhanden, so beziehen sich die genannten Werte für den Neutralisationsgrad der freien Carboxylgruppen auf die Summe aller vorhandenen Carboxylgruppen. If more than one polymer comprising free carboxyl groups is present, the values given for the degree of neutralization of the free carboxyl groups relate to the sum of all carboxyl groups present.
In der vorliegenden Beschreibung des oralen Dünnfilms kann „umfassend" auch „bestehend aus" bedeuten. In the present description of the oral thin film, "comprising" can also mean "consisting of".
Das mindestens eine Polymer, das freie Carboxylgruppen umfasst, ist vorzugsweise ein in Wasser schwer lösliches, sehr schwer lösliches oder praktisch unlösliches Polymer gemäß der folgenden Tabelle. The at least one polymer comprising free carboxyl groups is preferably a sparingly soluble, very sparingly soluble or practically insoluble polymer according to the table below.
Löslichkeit in Wasser bei 15 °C bis 25 °C:
Es hat sich gezeigt, dass die Löslichkeit von Polymeren, die freie Carboxylgruppen umfassen, in Wasser durch die Zugabe von mindestens einer Base variiert werden kann. Übertragen auf den oralen Dünnfilm bedeutet das, dass die Zerfallszeit des oralen Dünnfilms im Mund des Patienten ebenfalls durch Vorhandensein mindestens einer Base in dem oralen Dünnfilm leicht variiert werden kann. Solubility in water at 15°C to 25°C: It has been shown that the solubility of polymers containing free carboxyl groups in water can be varied by adding at least one base. Applied to the oral thin film, this means that the disintegration time of the oral thin film in the patient's mouth can also be easily varied by the presence of at least one base in the oral thin film.
Der erfindungsgemäße orale Dünnfilm ist ferner dadurch gekennzeichnet, dass die freien Carboxylgruppen des mindestens einen Polymers, das freie Carboxylgruppen umfasst, durch Zugabe mindestens einer Base, vorzugsweise NaOH, neutralisiert wurden. The oral thin film according to the invention is further characterized in that the free carboxyl groups of the at least one polymer comprising free carboxyl groups have been neutralized by adding at least one base, preferably NaOH.
Außer NaOH sind auch andere Alkali- oder Erdalkalihydroxide als Basen geeignet, beispielsweise KOH. In addition to NaOH, other alkali metal or alkaline earth metal hydroxides are also suitable as bases, for example KOH.
Die Menge der mindestens einen Base beträgt vorzugsweise von 1 bis 15 Gew.- %, insbesondere von 0,7 bis 3 Gew.-%, bezogen auf das Gewicht des mindestens einen Polymers, das freie Carboxylgruppen umfasst. The amount of the at least one base is preferably from 1 to 15% by weight, in particular from 0.7 to 3% by weight, based on the weight of the at least one polymer which comprises free carboxyl groups.
Die zugegebene Menge der mindestens einen Base wird vorzugsweise so bemessen, dass das Äquivalenzverhältnis der Base zu den freien Carboxylgruppen des mindestens einen Polymers, das freie Carboxylgruppen umfasst, 1:10 bis 2: 1, vorzugsweise 1:10 bis 1:1, beträgt. The amount of the at least one base added is preferably such that the equivalence ratio of the base to the free carboxyl groups of the at least one polymer comprising free carboxyl groups is 1:10 to 2:1, preferably 1:10 to 1:1.
Dem Fachmann ist hierbei klar, dass die Menge der eingesetzten Base auch von dem Molekulargewicht der Base sowie von deren Löslichkeit abhängt. It is clear to the person skilled in the art that the amount of base used also depends on the molecular weight of the base and on its solubility.
Das mindestens eine Polymer, das freie Carboxylgruppen umfasst, umfasst vorzugsweise ein Polymer auf Basis von (Meth)Acrylsäure und/oder auf Basis eines Copolymers von (Meth)Acrylsäure und (Meth)Acrylsäureestern. The at least one polymer, which comprises free carboxyl groups, preferably comprises a polymer based on (meth)acrylic acid and/or based on a copolymer of (meth)acrylic acid and (meth)acrylic acid esters.
Ganz besonders bevorzugt umfasst das mindestens eine Polymer, das freie Carboxylgruppen umfasst, ein Copolymer von (Meth)Acrylsäure und (Meth)Acrylsäureestern, ganz besonders bevorzugt ein (Meth)Acrylsäure/Ethylacrylat-Copolymer. Very particularly preferably, the at least one polymer comprising free carboxyl groups comprises a copolymer of (meth)acrylic acid and (meth)acrylic acid esters, very particularly preferably a (meth)acrylic acid/ethyl acrylate copolymer.
Geeignete Polymere sind beispielsweise unter den Handelsnamen Eudragit L (von Evonik) oder Kollicoat MAE (von BASF) erhältlich.
Diese Polymere haben den Vorteil, dass sie nahezu unlöslich in Wasser sind und diese Löslichkeit durch Zugabe von mindestens einer Base gut variiert werden kann. Ferner sind diese Polymere gut mit dem Wirkstoff Ketamin kompatibel. Suitable polymers are available, for example, under the trade names Eudragit L (from Evonik) or Kollicoat MAE (from BASF). These polymers have the advantage that they are almost insoluble in water and this solubility can be easily varied by adding at least one base. Furthermore, these polymers are well compatible with the active ingredient ketamine.
Der erfindungsgemäße orale Dünnfilm umfasst ferner vorzugsweise mindestens ein wasserlösliches Polymer. The oral thin film of the present invention preferably further comprises at least one water-soluble polymer.
Wasserlösliche Polymere umfassen chemisch sehr unterschiedliche, natürliche oder synthetische Polymere, deren gemeinsames Merkmal ihre Löslichkeit in Wasser oder wässrigen Medien ist. Voraussetzung ist, dass diese Polymere eine für die Wasserlöslichkeit ausreichende Anzahl an hydrophilen Gruppen besitzen und nicht vernetzt sind. Die hydrophilen Gruppen können nicht-ionisch, anionisch, kationisch und/oder zwitterionisch sein. Water-soluble polymers include chemically very different, natural or synthetic polymers whose common feature is their solubility in water or aqueous media. The prerequisite is that these polymers have a sufficient number of hydrophilic groups for water solubility and are not crosslinked. The hydrophilic groups can be non-ionic, anionic, cationic and/or zwitterionic.
Wasserlösliche Polymere weisen vorzugsweise eine Löslichkeit in Wasser gemäß der vorstehenden Tabelle von mindestens „löslich" auf. Water-soluble polymers preferably have a solubility in water according to the table above of at least "soluble".
Das mindestens eine wasserlösliche Polymer ist vorzugsweise ausgewählt aus Stärke und Stärkederivaten, Dextranen, Cellulosederivaten, wie Carboxymethylcellulose, Hydroxypropylcellulose, Hydroxyethylcellulose, Hydroxypropylmethylcellulose, Hydroxypropylethylcellulose, Natriumcarboxymethylcellulose, Ethyl- oder Propylcellulose, Polyacrylsäuren, Polyacrylaten, Polyvinylpyrrolidonen, Vinvlpyrrolidon/Vinylacetat-Copolymeren, Polyvinylalkoholen, Polyethylenoxidpolymeren, Polyacrylamiden, Polyethylenglycolen, Gelatine, Collagen, Alginaten, Pektin, Pullulan, Traganth, Chitosan, Alginsäure, Arabinogalaktan, Galaktomannan, Agar, Agarose, Carrageen und natürlichen Gummen. The at least one water-soluble polymer is preferably selected from starch and starch derivatives, dextrans, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates, polyvinylpyrrolidones, vinylpyrrolidone/vinyl acetate copolymers, polyvinyl alcohols, polyethylene oxide polymers , polyacrylamides, polyethylene glycols, gelatin, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums.
Die Zugabe eines solchen wasserlöslichen Polymers hat den Vorteil, dass die Kompabilität zwischen Film und Arzneistoff verbessert werden kann (z.B. auch zur Stabilisierung einer festen Lösung). Des Weiteren kann das zusätzliche Polymer als Füllstoff dienen, um z.B. ein bestimmtes Gewicht/Dicke des oralen Dünnfilms zu erreichen. The addition of such a water-soluble polymer has the advantage that the compatibility between the film and the drug can be improved (e.g. also to stabilize a solid solution). Furthermore, the additional polymer can serve as a filler, for example to achieve a certain weight/thickness of the oral thin film.
Der erfindungsgemäße orale Dünnfilm ist vorzugsweise dadurch gekennzeichnet, dass das mindestens eine wasserlösliche Polymer in einer Menge von 5 bis 40 Gew.-%, vorzugsweise von 8 bis 30 Gew.-%, besonders bevorzugt von 10 bis 25
Gew.-%, bezogen auf das Gesamtgewicht des oralen Dünnfilms, in dem oralen Dünnfilm vorhanden ist. The oral thin film according to the invention is preferably characterized in that the at least one water-soluble polymer is present in an amount of 5 to 40% by weight, preferably 8 to 30% by weight, particularly preferably 10 to 25% by weight % by weight based on the total weight of the oral thin film is present in the oral thin film.
In dem erfindungsgemäßen oralen Dünnfilm liegt Ketamin und/oder ein pharmazeutisch akzeptables Salz davon vor, bevorzugt Ketamin-HCl. Unter Ketamin wird hierbei (S)-(±)-2-(2-Chlorphenyl)-2-(methylamino)cyclohexan-l-on, (R)-(±)-2-(2-Chlorphenyl)-2-(methylamino)cyclohexan-l-on, sowie das Racemat (RS)-(±)-2-(2-Chlorphenyl)-2-(methylamino)cyclohexan-l-on verstanden. Ketamine and/or a pharmaceutically acceptable salt thereof, preferably ketamine-HCl, is present in the oral thin film of the present invention. Under ketamine, (S)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-l-one, (R)-(±)-2-(2-chlorophenyl)-2-( methylamino)cyclohexan-l-one, and the racemate (RS)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-l-one.
Besonders bevorzugt liegt jedoch (S)-Ketamin oder ein pharmazeutisch akzeptables Salz davon, insbesondere (S)-Ketamin-HCI, als einziges Stereoisomer von Ketamin vor, da die analgetische und anästhetische Potenz von (S)-Ketamin etwa dreifach höher als die der (R)-Form ist. However, (S)-ketamine or a pharmaceutically acceptable salt thereof, in particular (S)-ketamine-HCl, is particularly preferred as the sole stereoisomer of ketamine, since the analgesic and anesthetic potency of (S)-ketamine is approximately three-fold higher than that of (R) form.
Der erfindungsgemäße orale Dünnfilm ist ferner vorzugsweise dadurch gekennzeichnet, dass das Ketamin in einer Menge von 1 bis 50 Gew.-%, vorzugsweise von 10 bis 40 Gew.-%, besonders bevorzugt von 25 bis 35 Gew.-%, bezogen auf das Gesamtgewicht des oralen Dünnfilms, in dem oralen Dünnfilm vorhanden ist. The oral thin film of the present invention is further preferably characterized in that the ketamine is present in an amount of 1 to 50% by weight, preferably 10 to 40% by weight, more preferably 25 to 35% by weight based on the total weight of the oral thin film in which oral thin film is present.
Zudem ist der erfindungsgemäße orale Dünnfilm vorzugsweise dadurch gekennzeichnet, dass das mindestens eine Polymer, das freie Carboxylgruppen umfasst, in einer Menge von 1 bis 50 Gew.-%, vorzugsweise von 10 bis 40 Gew.- %, besonders bevorzugt von 25 bis 35 Gew.-%, bezogen auf das Gesamtgewicht des oralen Dünnfilms, in dem oralen Dünnfilm vorhanden ist. In addition, the oral thin film according to the invention is preferably characterized in that the at least one polymer comprising free carboxyl groups is present in an amount of 1 to 50% by weight, preferably 10 to 40% by weight, particularly preferably 25 to 35% by weight % based on the total weight of the oral thin film is present in the oral thin film.
Der erfindungsgemäße orale Dünnfilm ist vorzugsweise dadurch gekennzeichnet, dass der orale Dünnfilm mindestens einen Hilfsstoff ausgewählt aus der Gruppe, umfassend Farbstoffe, Weichmacher (wie Glycerin), Aromastoffe, Süßstoffe, geschmacksmaskierende Mittel, Emulgatoren, Enhancer, pH-Regulatoren, Feuchthaltemittel, Konservierungsmittel und/oder Antioxidationsmittel, umfasst. The oral thin film according to the invention is preferably characterized in that the oral thin film contains at least one excipient selected from the group comprising dyes, plasticizers (such as glycerin), flavorings, sweeteners, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and/or or antioxidants.
Jeder dieser Hilfsstoffe ist vorzugsweise jeweils in einer Menge von etwa 0,1 bis 10 Gew.-%, bezogen auf das Gesamtgewicht des oralen Dünnfilms, in dem oralen Dünnfilm enthalten. Each of these excipients is preferably contained in the oral thin film in an amount of about 0.1 to 10% by weight based on the total weight of the oral thin film.
Der erfindungsgemäße orale Dünnfilm besitzt vorzugsweise eine Fläche von etwa 0,5 cm2 bis etwa 10 cm2, besonders bevorzugt von etwa 2 cm2 bis etwa 8 cm2.
Der erfindungsgemäße orale Dünnfilm ist vorzugsweise dadurch gekennzeichnet, dass das Flächengewicht des oralen Dünnfilms etwa 50 bis 300 g/m2, vorzugsweise etwa 100 bis 200 g/m2, beträgt. The oral thin film of the present invention preferably has an area of from about 0.5 cm 2 to about 10 cm 2 , more preferably from about 2 cm 2 to about 8 cm 2 . The oral thin film of the present invention is preferably characterized in that the basis weight of the oral thin film is about 50 to 300 g/m 2 , preferably about 100 to 200 g/m 2 .
Dies entspricht vorzugsweise einer Schichtdicke von vorzugsweise etwa 20 pm bis etwa 500 pm, besonders bevorzugt von etwa 50 pm bis etwa 300 pm. This preferably corresponds to a layer thickness of preferably about 20 μm to about 500 μm, particularly preferably from about 50 μm to about 300 μm.
Der erfindungsgemäße orale Dünnfilm löst sich in der Mundhöhle vorzugsweise in einem Zeitraum von mehr als etwa 10 min, bevorzugt in einem Zeitraum von mehr als etwa 20 min, besonders bevorzugt in einem Zeitraum von 20 bis 40 min auf. The oral thin film of the present invention preferably dissolves in the oral cavity in a period greater than about 10 minutes, more preferably in a period greater than about 20 minutes, more preferably in a period of 20 to 40 minutes.
Die vorliegende Erfindung betrifft ferner ein Verfahren zur Herstellung des erfindungsgemäßen oralen Dünnfilms. Das Verfahren umfasst die Schritte a) Herstellen einer Lösung, bevorzugt auf Basis einer Mischung umfassend Wasser und/oder mindestens ein organisches Lösemittel, wie Ethanol, umfassend Ketamin, mindestens ein Polymer, das freie Carboxylgruppen umfasst, wobei 10 bis 100% der freien Carboxylgruppen des mindestens einen Polymers, das freie Carboxylgruppen umfasst, neutralisiert als Salz vorliegen, sowie, falls vorhanden, die weiteren Inhaltstoffe; b) Ausstreichen und Trocknen der gemäß Schritt a) erhaltenen Lösung, so dass die getrocknete Lösung vorzugsweise ein Flächengewicht von etwa 50 bis etwa 300 g/m2 aufweist. The present invention further relates to a method for producing the oral thin film of the present invention. The method comprises the steps a) preparing a solution, preferably based on a mixture comprising water and/or at least one organic solvent, such as ethanol, comprising ketamine, at least one polymer comprising free carboxyl groups, with 10 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups, present in neutralized form as a salt, and, if present, the other ingredients; b) spreading out and drying the solution obtained according to step a), so that the dried solution preferably has a basis weight of about 50 to about 300 g/m 2 .
In einer bevorzugten Ausgestaltung des erfindungsgemäßen Verfahrens, ist der Schritt a) wie folgt ausgestaltet. a) Herstellen einer Lösung, bevorzugt auf Basis einer Mischung umfassend Wasser und/oder mindestens ein organisches Lösemittel, wie Ethanol, umfassend Ketamin, mindestens eine Base, bevorzugt NaOH, und das mindestens eine Polymer, das freie Carboxylgruppen umfasst, sowie, falls vorhanden, die weiteren Inhaltstoffe. In a preferred embodiment of the method according to the invention, step a) is designed as follows. a) preparing a solution, preferably based on a mixture comprising water and/or at least one organic solvent such as ethanol, comprising ketamine, at least one base, preferably NaOH, and the at least one polymer comprising free carboxyl groups, and, if present, the other ingredients.
Dabei wird das mindestens ein Polymer, das freie Carboxylgruppen umfasst durch Zugabe von mindestens einer Base direkt in der Lösung teilweise neutralisiert.
Alle bevorzugten Ausführungsformen und Definitionen für den erfindungsgemäßen oralen Dünnfilm gelten analog für das erfindungsgemäße Verfahren. In this case, the at least one polymer, which comprises free carboxyl groups, is partially neutralized directly in the solution by adding at least one base. All preferred embodiments and definitions for the oral thin film according to the invention apply analogously to the method according to the invention.
Die vorliegende Erfindung betrifft ferner einen oralen Dünnfilm erhältlich nach dem vorstehend beschriebenen Verfahren. The present invention further relates to an oral thin film obtainable by the method described above.
Außerdem betrifft die vorliegende Erfindung einen oralen Dünnfilm, wie vorstehend beschrieben oder erhältlich nach dem vorstehend beschriebenen Verfahren, als Arzneimittel. In addition, the present invention relates to an oral thin film as described above or obtainable by the method described above as a medicament.
Die vorliegende Erfindung betrifft zudem einen oralen Dünnfilm, wie vorstehend beschrieben oder erhältlich nach dem vorstehend beschriebenen Verfahren, als Arzneimittel zur Verwendung in der Behandlung von Schmerz und/oder Depressionen, insbesondere zur Reduzierung des Suizidrisikos und/oder zur Verwendung als Allgemeinanästhetikum, vorzugsweise zur Einleitung und Durchführung einer Vollnarkose oder als Ergänzung bei Regionalanästhesien und/oder als Analgetikum. The present invention also relates to an oral thin film as described above or obtainable by the method described above as a medicament for use in the treatment of pain and/or depression, in particular for reducing the risk of suicide and/or for use as a general anaesthetic, preferably for induction and administration of general anesthesia or as an adjunct to regional anesthesia and/or as an analgesic.
Die vorstehend für den erfindungsgemäßen Dünnfilm aufgeführten bevorzugten Ausführungsformen gelten auch für das erfindungsgemäße Verfahren, den mit diesem erhaltenen oralen Dünnfilm und für dessen Verwendung als Arzneimittel. The preferred embodiments listed above for the thin film according to the invention also apply to the method according to the invention, the oral thin film obtained with this and for its use as a medicament.
Beschreibung der Figuren Description of the figures
Figur 1 zeigt die Permeationsdaten der Formulierungen gemäß Tabelle 1. Figure 1 shows the permeation data of the formulations according to Table 1.
Figur 2 zeigt die in vitro Freisetzungsdaten der Formulierungen gemäß Tabelle 1. Figure 2 shows the in vitro release data of the formulations according to Table 1.
Die Erfindung wird nachfolgend anhand von nicht beschränkenden Beispielen näher erläutert.
Beispiele The invention is explained in more detail below using non-limiting examples. examples
Kollidon VA 64: Polyvinylpyrrolidon von BASF Kollidon VA 64: polyvinylpyrrolidone from BASF
Kollicoat MAE: (Meth)Acrylsäure/Ethylacrylat-Copolymer von BASF Kollicoat MAE: (meth)acrylic acid/ethyl acrylate copolymer from BASF
Die oralen Dünnfilme der Zusammensetzungen gemäß der obigen Tabelle wurden wie folgt hergestellt: The oral thin films of the compositions according to the table above were prepared as follows:
Das Lösemittel wird vorgelegt und die Inhaltsstoffe gemäß Tabelle 1 nacheinander gelöst. Die Masse wird nun ruhen gelassen bis sie blasenfrei ist. Die Masse wird auf einen silikonisierten Liner aufgebracht und der daraus resultierende Film wird getrocknet. The solvent is introduced and the ingredients according to Table 1 are dissolved one after the other. The mass is now left to rest until it is bubble-free. The mass is applied to a siliconized liner and the resulting film is dried.
Für diese Formulierungen wurden die Permeation des Wirkstoffs gemäß dem folgenden Verfahren ermittelt. For these formulations, the permeation of the active ingredient was determined according to the following procedure.
Die folgenden Testreihen mit den jeweils ausgewählten Wirkstoffen wurden im Rahmen einer typischen in wiro-Permeation mittels Multiwell-Platten bei 37°C durchgeführt. Zu vorbestimmten Wechselzeiten wurde das jeweils verwendete Akzeptormedium komplett durch ein Neues ausgetauscht und der Gehalt an permeierter Wirkstoffmenge in diesen Akzeptorlösungen mittels HPLC bestimmt. The following series of tests with the active substances selected in each case were carried out as part of a typical in vitro permeation using multiwell plates at 37°C. At predetermined exchange times, the acceptor medium used in each case was completely replaced with a new one and the amount of permeated active ingredient in these acceptor solutions was determined by means of HPLC.
Als Hautmodell wurde Speiseröhren-Mukosa (Hausschwein) mit einer Schichtdicke von 400 pm pm verwendet.
Als Akzeptormedium wurde Phosphatpuffer pH 7,4 eingesetzt. Esophageal mucosa (domestic pig) with a layer thickness of 400 μm was used as a skin model. Phosphate buffer pH 7.4 was used as the acceptor medium.
Die Vergleichsmessung erfolgte gegen die schnellfreisetzende Schaumformulierung (140Kea0002) eingesetzt, die eine Zusammensetzung gemäß der folgenden Tabelle aufweist.
The comparison measurement was carried out against the quick-release foam formulation (140Kea0002) used, which has a composition according to the table below.
In Figur 1 ist zu sehen, dass sich bei den Formulierungen 140Kea0041 (1 % NaOH), 140Kea0043 (2 % NaOH), 140Kea0044 (2.8 % NaOH) mit steigendem NaOH-Anteil sich die Permeation signifikant verlangsamt bis sie bei der Formulierung 140Kea0047 (9 % NaOH) stagniert. Figure 1 shows that in the formulations 140Kea0041 (1% NaOH), 140Kea0043 (2% NaOH), 140Kea0044 (2.8% NaOH) the permeation slows down significantly with increasing NaOH content until it is in the formulation 140Kea0047 (9th % NaOH) stagnates.
Die Zerfallszeit wurde in einem weiteren Versuch getestet und bestätigte die Ergebnisse die in der Permeation gezeigt wurden. Dabei wurde gezeigt, dass die Formulierung 140Kea0041 (1% NaOH) die höchste Zerfallszeit aufwies, was mit der langsamsten Freisetzung korreliert. The disintegration time was tested in a further experiment and confirmed the results shown in the permeation. The formulation 140Kea0041 (1% NaOH) was shown to have the highest disintegration time, which correlates with the slowest release.
Die Zerfallszeit der oralen Dünnfilme wurde mittels der USP Methode <701> Disintegration, aus 2016 gemessen. The disintegration time of the oral thin films was measured using the USP Method <701> Disintegration, from 2016.
Verwendete Apparatur: Zerfallstester DIST 3 mit Zerfallskörbchen Apparatus used: disintegration tester DIST 3 with disintegration basket
Anzahl Hübe pro Minute: 29 - 32 Number of strokes per minute: 29 - 32
Medium: Wasser Medium: water
Temperatur: 37 °C ± 2 °C Temperature: 37ºC ± 2ºC
Endpunktbestimmung: Visuell Endpoint Determination: Visual
Endpunkt: Totaler Zerfall des Films End point: total disintegration of the film
Die Ergebnisse der Zerfallszeitmessung sind in Tabelle 2 zusammengefasst.
Tabelle 2: Zerfallszeitmessung
The results of the disintegration measurement are summarized in Table 2. Table 2: Decay time measurement
In einer in vitro Freisetzungsuntersuchung konnte neben dem verlangsamten Zerfall auch die verlangsamte Wirkstofffreisetzung gezeigt werden. In an in vitro release study, it was possible to show not only the slower decay but also the slower release of the active ingredient.
Die in vitro Freisetzung wurde wie folgt ermittelt: The in vitro release was determined as follows:
Bei der in-vitro Freisetzung wird S-Ketamin aus dem oralen Dünnfilmen (OTF) freigesetzt und bestimmt. Der Wirkstoff wird in Phosphatpuffer pH 6.8 USP freigesetzt und dann durch eine Gradienten-Umkehrphasen HPLC-Methode bestimmt. Die Quantifizierung erfolgte gegen einen externen Standard. During the in-vitro release, S-ketamine is released from the oral thin film (OTF) and determined. The drug is released in phosphate buffer pH 6.8 USP and then determined by a gradient reverse phase HPLC method. The quantification was carried out against an external standard.
Die Freisetzung wird mit Dissolution Apparatus 2 - (Paddle over sinker) gemäß USP <711 > durchgeführt. Dissolution is performed with Dissolution Apparatus 2 - (Paddle over sinker) according to USP <711>.
Die Ergebnisse der in vitro Freisetzung sind in Figur 2 gezeigt. Hier zeigte wieder die Formulierung 140Kea0041 (1% NaOH) die langsamste Freisetzung.
The in vitro release results are shown in FIG. Here again the formulation 140Kea0041 (1% NaOH) showed the slowest release.
Claims
1. Oraler Dünnfilm, umfassend Ketamin oder ein pharmazeutisch akzeptables Salz davon, mindestens ein Polymer, das freie Carboxylgruppen umfasst, wobei 10 bis 100% der freien Carboxylgruppen des mindestens einen Polymers, das freie Carboxylgruppen umfasst, neutralisiert als Salz vorliegen. An oral thin film comprising ketamine or a pharmaceutically acceptable salt thereof, at least one polymer comprising free carboxyl groups, wherein 10 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized as a salt.
2. Oraler Dünnfilm gemäß Anspruch 1, wobei die freien Carboxylgruppen des mindestens einen Polymers, das freie Carboxylgruppen umfasst, durch Zugabe mindestens einer Base, vorzugsweise NaOH, neutralisiert wurden. 2. Oral thin film according to claim 1, wherein the free carboxyl groups of the at least one polymer comprising free carboxyl groups have been neutralized by the addition of at least one base, preferably NaOH.
3. Oraler Dünnfilm gemäß irgendeinem der vorhergehenden Ansprüche, wobei das mindestens eine Polymer, das freie Carboxylgruppen umfasst, ein Polymer auf Basis von (Meth)Acrylsäure und/oder auf Basis eines Copolymers von (Meth)Acrylsäure und (Meth)Acrylsäureestern umfasst. 3. Oral thin film according to any one of the preceding claims, wherein the at least one polymer comprising free carboxyl groups comprises a polymer based on (meth)acrylic acid and/or based on a copolymer of (meth)acrylic acid and (meth)acrylic acid esters.
4. Oraler Dünnfilm gemäß Anspruch 3, wobei das mindestens eine Polymer, das freie Carboxylgruppen umfasst, ein (Meth)Acrylsäure/Ethylacrylat-Copolymer umfasst. The oral thin film of claim 3, wherein the at least one polymer comprising free carboxyl groups comprises a (meth)acrylic acid/ethyl acrylate copolymer.
5. Oraler Dünnfilm gemäß irgendeinem der vorhergehenden Ansprüche, wobei der orale Dünnfilm ferner mindestens ein wasserlösliches Polymer umfasst. 5. The oral thin film according to any one of the preceding claims, wherein the oral thin film further comprises at least one water soluble polymer.
6. Oraler Dünnfilm gemäß Anspruch 5, wobei das mindestens eine wasserlösliche Polymer ausgewählt ist aus Stärke und Stärkederivaten,6. Oral thin film according to claim 5, wherein the at least one water-soluble polymer is selected from starch and starch derivatives,
Dextranen, Cellulosederivaten, wie Carboxymethylcellulose, Hydroxypropylcellulose, Hydroxyethylcellulose, Hydroxypropylmethylcellulose, Hydroxypropylethylcellulose, Natriumcarboxymethylcellulose, Ethyl- oder Propylcellulose, Polyacrylsäuren, Polyacrylaten, Polyvinyl pyrrolidonen, Vinvlpyrrolidon/Vinylacetat-Copolymeren, Polyvinylalkoholen, Polyethylenoxidpolymeren, Polyacrylamiden, Polyethylenglycolen, Gelatine, Collagen, Alginaten, Pektin, Pullulan, Traganth, Chitosan, Alginsäure, Arabinogalaktan, Galaktomannan, Agar, Agarose, Carrageen und natürlichen Gummen.
Dextrans, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates, polyvinyl pyrrolidones, vinyl pyrrolidone/vinyl acetate copolymers, polyvinyl alcohols, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatin, collagen, alginates, pectin , pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums.
7. Oraler Dünnfilm gemäß irgendeinem der vorhergehenden Ansprüche, wobei die mindestens eine Base ein Hydroxid, vorzugsweise NaOH, umfasst. 7. Oral thin film according to any one of the preceding claims, wherein the at least one base comprises a hydroxide, preferably NaOH.
8. Oraler Dünnfilm gemäß irgendeinem der vorhergehenden Ansprüche, wobei das Ketamin (S)-Ketamin oder ein pharmazeutisch akzeptables Salz davon umfasst. 8. An oral thin film according to any one of the preceding claims, wherein the ketamine comprises (S)-ketamine or a pharmaceutically acceptable salt thereof.
9. Oraler Dünnfilm gemäß irgendeinem der vorhergehenden Ansprüche, wobei das Ketamin in einer Menge von 1 bis 50 Gew.-%, vorzugsweise von 10 bis 40 Gew.-%, bezogen auf das Gesamtgewicht des oralen Dünnfilms, in dem oralen Dünnfilm vorhanden ist. 9. An oral thin film according to any one of the preceding claims, wherein the ketamine is present in the oral thin film in an amount of 1 to 50% by weight, preferably 10 to 40% by weight, based on the total weight of the oral thin film.
10. Oraler Dünnfilm gemäß irgendeinem der vorhergehenden Ansprüche, wobei das mindestens eine Polymer, das freie Carboxylgruppen umfasst, in einer Menge von 1 bis 50 Gew.-%, vorzugsweise von 10 bis 40 Gew.-%, bezogen auf das Gesamtgewicht des oralen Dünnfilms, in dem oralen Dünnfilm vorhanden ist. 10. Oral thin film according to any one of the preceding claims, wherein the at least one polymer comprising free carboxyl groups in an amount of 1 to 50% by weight, preferably 10 to 40% by weight, based on the total weight of the oral thin film , in which oral thin film is present.
11. Oraler Dünnfilm gemäß irgendeinem der Ansprüche 2 bis 10, wobei mindestens 10% bis 100% der freien Carboxylgruppen des mindestens einen Polymers, das freie Carboxylgruppen umfasst, neutralisiert als Salz der mindestens einen Base vorliegen. 11. The oral thin film of any one of claims 2 to 10, wherein at least 10% to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized as a salt of the at least one base.
12. Oraler Dünnfilm gemäß irgendeinem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass der orale Dünnfilm ferner mindestens einen Hilfsstoff ausgewählt aus der Gruppe, umfassend Farbstoffe, Aromastoffe, Süßstoffe, Weichmacher, geschmacksmaskierende Mittel, Emulgatoren, Enhancer, pH-Regulatoren, Feuchthaltemittel, Konservierungsmittel und/oder Antioxidationsmittel, umfasst. 12. Oral thin film according to any one of the preceding claims, characterized in that the oral thin film further contains at least one excipient selected from the group comprising colorants, flavorings, sweeteners, plasticizers, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and /or antioxidants.
13. Oraler Dünnfilm gemäß irgendeinem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass das Flächengewicht des oralen Dünnfilms etwa 50 bis 300 g/m2 beträgt. 13. Oral thin film according to any one of the preceding claims, characterized in that the basis weight of the oral thin film is about 50 to 300 g/m 2 .
14. Verfahren zur Herstellung eines oralen Dünnfilms gemäß irgendeinem der Ansprüche 1 bis 13, umfassend die Schritte: a) Herstellen einer Lösung umfassend Ketamin, mindestens eine Base und das mindestens eine Polymer, das freie Carboxylgruppen umfasst;
b) Ausstreichen und Trocknen der gemäß Schritt a) erhaltenen Lösung . 14. A method for preparing an oral thin film according to any one of claims 1 to 13, comprising the steps of: a) preparing a solution comprising ketamine, at least one base and the at least one polymer comprising free carboxyl groups; b) spreading out and drying the solution obtained in step a).
15. Verwendung eines oralen Dünnfilms gemäß irgendeinem der Ansprüche 1 bis 13 als Arzneimittel, vorzugsweise in der Behandlung von Schmerzen und/oder Depressionen.
15. Use of an oral thin film according to any one of claims 1 to 13 as a medicament, preferably in the treatment of pain and/or depression.
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Citations (3)
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DE102005007059A1 (en) * | 2005-02-15 | 2006-08-24 | Röhm GmbH & Co. KG | Partially neutralized anionic (meth) acrylate copolymer |
WO2020086673A1 (en) * | 2018-10-26 | 2020-04-30 | Guangzhou Dazhou Biomedicine Ltd. | Ketamine oral transmucosal delivery system |
WO2021123289A1 (en) * | 2019-12-20 | 2021-06-24 | Lts Lohmann Therapie-Systeme Ag | Soluble rear layer for otf |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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DE102005007059A1 (en) * | 2005-02-15 | 2006-08-24 | Röhm GmbH & Co. KG | Partially neutralized anionic (meth) acrylate copolymer |
WO2020086673A1 (en) * | 2018-10-26 | 2020-04-30 | Guangzhou Dazhou Biomedicine Ltd. | Ketamine oral transmucosal delivery system |
WO2021123289A1 (en) * | 2019-12-20 | 2021-06-24 | Lts Lohmann Therapie-Systeme Ag | Soluble rear layer for otf |
Non-Patent Citations (1)
Title |
---|
SOLOMONIDOU D ET AL: "Effect of carbomer concentration and degree of neutralization on the mucoadhesive properties of polymer films", JOURNAL OF BIOMATERIALS SCIENCE. POLYMER EDITION, VSP, UTRECHT, NL, vol. 12, no. 11, 1 January 2001 (2001-01-01), pages 1191 - 1205, XP009028488, ISSN: 0920-5063, DOI: 10.1163/156856201753395743 * |
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