WO2024067731A1 - S-氯胺酮经皮组合物及其制备方法和应用 - Google Patents
S-氯胺酮经皮组合物及其制备方法和应用 Download PDFInfo
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- WO2024067731A1 WO2024067731A1 PCT/CN2023/122172 CN2023122172W WO2024067731A1 WO 2024067731 A1 WO2024067731 A1 WO 2024067731A1 CN 2023122172 W CN2023122172 W CN 2023122172W WO 2024067731 A1 WO2024067731 A1 WO 2024067731A1
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- ketamine
- acid
- transdermal composition
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- 230000036556 skin irritation Effects 0.000 description 1
- 231100000245 skin permeability Toxicity 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
-
- 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
-
- 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
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- 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
Definitions
- the present invention relates to the field of pharmaceutical preparations, and in particular to an S-ketamine transdermal composition, an S-ketamine transdermal patch, and a preparation method and application thereof.
- Ketamine a derivative of phencyclidine (Pce) is a high-affinity, non-competitive NMDA receptor antagonist that can be used clinically as a psychiatric drug to treat depression.
- NMDA receptors a racemic form
- R-ketamine a racemic form
- S-ketamine and R-ketamine two enantiomers
- the affinity of S-ketamine for NMDA receptors, opioid receptors, and M cholinergic receptors is about 2-4 times higher than that of R-ketamine, and the side effects such as hallucinations and dreams in clinical applications are mainly caused by the R-isomer. Therefore, compared with racemic ketamine and R-ketamine, S-ketamine has better efficacy and less side effects such as hallucinations and addiction.
- the present invention provides an S-ketamine transdermal composition, as well as a preparation method and application of the transdermal composition.
- the transdermal composition provided by the present invention can provide a flux of active ingredients as high as possible.
- the transdermal composition can slowly release the drug within 2 to 3 days of use, has a sustained in vitro release characteristic, and has a more stable relationship curve between the plasma concentration and time in the body over a longer period of time.
- the S-ketamine transdermal composition provided by the present invention is non-irritating to human skin and has good product stability; moreover, there is no risk of abuse due to an increased S-ketamine dosage or an increased frequency of administration.
- the present invention provides an S-ketamine transdermal composition, which comprises S-ketamine or a pharmaceutically acceptable salt thereof, a pressure-sensitive adhesive and a penetration enhancer;
- the pressure-sensitive adhesive is an acrylate pressure-sensitive adhesive without functional group substitution; and
- the penetration enhancer comprises a fatty acid and a fatty acid ester.
- S-ketamine has a chemical structure shown in formula (I):
- the content of S-ketamine is used for calculation.
- the content in the present invention is a weight percentage.
- the pressure-sensitive adhesive used in the present invention is usually a wet adhesive with a certain acrylate pressure-sensitive adhesive solid content, so the content of the acrylate pressure-sensitive adhesive is calculated by its solid content weight.
- the content of S-ketamine is 10%-20% by weight. In another embodiment, the content of S-ketamine is 10%-18% or 11%-20%. In another embodiment, the content of S-ketamine is 10%-15%, 11%-18% or 13%-20%. In another embodiment, the content of S-ketamine is 10%-13%, 11%-15% or 13%-18%. In another embodiment, the content of S-ketamine is 10%-11%, 11%-13% or 13%-15%. In another embodiment, the content of S-ketamine is 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17% or 19%.
- the content of the pressure-sensitive adhesive is 30%-75%. In another embodiment, the content of the pressure-sensitive adhesive is 30%-60% or 45%-75%. In another embodiment, the content of the pressure-sensitive adhesive is 45%-60% or 60%-75%. In another embodiment, the content of the pressure-sensitive adhesive is 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% or 61%.
- the non-functional substituted acrylate pressure-sensitive adhesive is selected from 87-4098 (an acrylate copolymer without functional group substitution, with ethyl acetate as solvent, solid content of 38.5%, containing vinyl acetate, and viscosity of 6500 cP), 87-900A (an acrylate copolymer without functional group substitution, with ethyl acetate as solvent, solid content of 43%, no vinyl acetate, and viscosity of 1800 cP), 87-9301 (an acrylate copolymer without functional group substitution, with ethyl acetate as solvent, solid content of 36.5%, no vinyl acetate, and viscosity of 9500 cP), GMS 3083 (an acrylate copolymer without functional group substitution, with ethyl acetate as solvent, solid content of 38%, no vinyl acetate, and viscosity of 8500 cP), One or more of GMS 3253 (an acrylate copolymer without functional group
- the non-functional substituted acrylate pressure-sensitive adhesive is selected from 87-4098.
- the content of the penetration enhancer is 5%-40%. In another embodiment, the content of the penetration enhancer is 5%-35% or 8%-40%. In another embodiment, the content of the penetration enhancer is 5%-30%, 8%-35% or 10%-40. In another embodiment, the content of the penetration enhancer is 5%-25%, 8%-30%, 10%-35% or 15%-40. In another embodiment, the content of the penetration enhancer is 5%-15%, 8%-25%, 10%-30%, 15%-35% or 25%-40%. In another embodiment, the content of the penetration enhancer is 8%-15%, 10%-25%, 15%-30% or 25%-35%. In another embodiment, the content of the penetration enhancer is 15%-25%. In yet another embodiment, the penetration enhancer is present in an amount of 17%, 18%, 19%, 20%, 21%, 22% or 23%.
- the weight ratio of the pressure-sensitive adhesive to the penetration enhancer is In another embodiment, the weight ratio of the pressure sensitive adhesive to the penetration enhancer is (1:1)-(4:1) or (2:1)-(5:1). In yet another embodiment, the weight ratio of the pressure sensitive adhesive to the penetration enhancer is (1:1)-(3:1), (2:1)-(4:1) or (3:1)-(5:1). In yet another embodiment, the weight ratio of the pressure sensitive adhesive to the penetration enhancer is 2:1, 3:1 or 4:1.
- the penetration enhancer comprises fatty acids and fatty acid esters. In some embodiments of the present invention, the penetration enhancer consists of fatty acids and fatty acid esters.
- the content of the fatty acid is 5%-35%. In another embodiment, the content of the fatty acid is 5%-25% or 10%-30%. In another embodiment, the content of the fatty acid is 5%-20%, 10%-25% or 15%-30%. In another embodiment, the content of the fatty acid is 5%-15%, 10%-20%, 15%-25% or 20%-30%. In another embodiment, the content of the fatty acid is 10%-20%, 15%-20% or 20%-25%. Also in one embodiment, the content of the fatty acid is 17%, 18%, 19%, 20%, 21%, 22% or 23%.
- the fatty acid ester is present in an amount of 1% to 10% based on the total weight of the transdermal composition. In another embodiment, the fatty acid ester is present in an amount of 1% to 8% or 3% to 10%. In yet another embodiment, the fatty acid ester is present in an amount of 1% to 5%, 3% to 8% or 5% to 10%. In yet another embodiment, the fatty acid ester is present in an amount of 1%, 2%, 3%, 4% or 5%.
- the weight ratio of the fatty acid to the fatty acid ester is (1:1)-(7:1). In another embodiment, the weight ratio of the fatty acid to the fatty acid ester is (1:1)-(6:1) or (2:1)-(7:1). In another embodiment, the weight ratio of the fatty acid to the fatty acid ester is (2:1)-(6:1) or (3:1)-(7:1). In another embodiment, the weight ratio of the fatty acid to the fatty acid ester is (3:1)-(6:1) or (4:1)-(7:1). In another embodiment, the weight ratio of the fatty acid to the fatty acid ester is (4:1)-(6:1) or (5:1)-(7:1).
- the weight ratio of the fatty acid to the fatty acid ester is (5:1)-(6:1) or (6:1)-(7:1). In yet another embodiment, the weight ratio of the fatty acid to the fatty acid ester is 5:1, 6:1 or 7:1.
- the fatty acid is selected from one or more of levulinic acid, valeric acid, caproic acid, caprylic acid, nonanoic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, 3-methylbutyric acid, neoheptanoic acid, neononanoic acid, isostearic acid, oleic acid, palmitoleic acid, linolenic acid, 11-octadecenoic acid, petroselinic acid, elaidic acid, arachidonic acid, gadoleic acid, and erucic acid.
- the fatty acid is selected from levulinic acid.
- the fatty acid ester is selected from one or more of lauryl lactate, methyl propionate, methyl valerate, diethyl sebacate, methyl laurate, ethyl laurate, propyl laurate, ethyl oleate, isopropyl oleate, isopropyl caprate, isopropyl myristate, isopropyl palmitate, propylene glycol monocaprylate, and diisopropyl adipate.
- the fatty acid ester is selected from lauryl lactate.
- the S-ketamine transdermal composition further comprises a crystallization inhibitor.
- the content of the crystallization inhibitor is 5%-30% based on the total weight of the transdermal composition. In another embodiment, the content of the crystallization inhibitor is 5%-20% or 10%-30%. In another embodiment, the content of the crystallization inhibitor is 5%-15%, 10%-20% or 15%-30%. In another embodiment, the content of the crystallization inhibitor is 5%-10%, 10%-15% or 15%-20%. In another embodiment, the content of the crystallization inhibitor is 10%, 11%, 12%, 13%, 14% or 15%.
- the weight ratio of the S-ketamine to the crystallization inhibitor is (1:3)-(4:1). In another embodiment, the weight ratio of S-ketamine to the crystallization inhibitor is (1:3)-(2:1) or (1:2)-(4:1). In another embodiment, the weight ratio of S-ketamine to the crystallization inhibitor is (1:3)-(1:1), (1:2)-(2:1) or (1:1)-(4:1). In yet another embodiment, the weight ratio of S-ketamine to the crystallization inhibitor is (1:2)-(1:1) or (1:1)-(2:1). In yet another embodiment, the weight ratio of S-ketamine to the crystallization inhibitor is 1:2, 1:1, 2:1 or 3:1.
- the crystallization inhibitor is selected from one or more of polymethacrylate, polyvinyl pyrrolidone polymer, cross-linked polyvinyl pyrrolidone polymer, polyvinyl pyrrolidone copolymer, polyvinyl pyrrolidone/vinyl acetate copolymer, cellulose-based polymer, polycarboxylic acid polymer, polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam graft copolymer (PVAc-PVCap-PEG).
- the crystallization inhibitor is selected from polymethacrylate. In some embodiments, the crystallization inhibitor is B.
- the S-ketamine transdermal composition comprises S-ketamine, levulinic acid, lauryl lactate, and 87-4098; the weight ratio of levulinic acid to lauryl lactate is (1:1)-(7:1), the content of S-ketamine is 10%-20%, the The content of 87-4098 is 30%-75%.
- the S-ketamine transdermal composition comprises S-ketamine, levulinic acid, lauryl lactate, 87-4098 and B; the weight ratio of levulinic acid to lauryl lactate is (1:1)-(7:1), the S-ketamine and the The weight ratio of B is (1:3)-(4:1), the content of S-ketamine is 10%-20%, and the The content of 87-4098 is 30%-75%.
- the present invention provides an S-ketamine transdermal patch, which comprises a backing layer, a drug-containing matrix layer and a release film layer, wherein the drug-containing matrix layer comprises the above-mentioned S-ketamine transdermal composition.
- the drug-containing matrix layer is a skeleton-type structure.
- the thickness of the drug-containing matrix layer is 50 ⁇ m-150 ⁇ m. In another embodiment, the thickness of the drug-containing matrix layer is 50 ⁇ m, 75 ⁇ m, 100 ⁇ m, 125 ⁇ m or 150 ⁇ m.
- the material of the backing layer of the transdermal patch is selected from one or more of polyethylene-aluminum-polyester/ethylene-vinyl acetate composite films, aluminum-polyester films, polyester-polyethylene composite films, multilayer polyester films and polyester-ethylene vinyl acetate composite films.
- the material of the backing layer of the transdermal patch is selected from polyethylene-aluminum-polyester/ethylene-vinyl acetate composite film.
- the material of the release film layer of the transdermal patch is selected from one or more of aluminum foil-silicone grease composite, siliconized polyester film, fluoropolymer coated polyester film, siliconized aluminum foil and silicone oil paper.
- the material of the release film layer of the transdermal patch is selected from aluminum foil-silicone grease composite.
- the present invention provides a method for preparing the aforementioned S-ketamine transdermal patch, comprising the following steps:
- the method for preparing the transdermal patch comprises the following steps:
- the solvent is ethyl acetate or anhydrous ethanol.
- the present invention also provides use of the aforementioned S-ketamine transdermal composition or the aforementioned S-ketamine transdermal patch in the preparation of a pharmaceutical preparation for treating depression.
- the depression is refractory depression or major depressive disorder in adults.
- the continuous administration time of the S-ketamine transdermal composition or the S-ketamine transdermal patch can reach 24 hours to 96 hours or more.
- the S-ketamine transdermal composition or the S-ketamine transdermal patch can be continuously administered for 24 hours or more.
- the S-ketamine transdermal composition or the S-ketamine transdermal patch can be continuously administered for 48 hours or more.
- the S-ketamine transdermal composition or the S-ketamine transdermal patch can be continuously administered for 72 hours or more.
- the S-ketamine transdermal composition or the S-ketamine transdermal patch can be continuously administered for 96 hours or more.
- the S-ketamine transdermal composition or the S-ketamine transdermal patch is administered once a day, once every two days, once every three days, once every four days, or once more frequently.
- the present invention also provides a method for treating depression, wherein the method comprises administering the aforementioned S-ketamine transdermal composition or transdermal patch to an individual.
- the depression is refractory depression or major depressive disorder in adults.
- the S-ketamine transdermal composition or the S-ketamine transdermal patch can be continuously administered for 24 hours to 96 hours or more.
- the S-ketamine transdermal composition or the S-ketamine transdermal patch can be continuously administered for 24 hours or more.
- the S-ketamine transdermal composition or the S-ketamine transdermal patch can be continuously administered for 48 hours or more.
- the S-ketamine transdermal composition or the S-ketamine transdermal patch can be continuously administered for 72 hours or more.
- the S-ketamine transdermal composition or the S-ketamine transdermal patch can be continuously administered for 96 hours or more.
- the S-ketamine transdermal composition or the S-ketamine transdermal patch is administered once a day, once every two days, once every three days, once every four days or more frequently.
- the acrylic pressure-sensitive adhesive without functional group substitution constitutes the skeleton structure of the transdermal composition.
- the solubility of S-ketamine in the skeleton material is improved.
- the S-ketamine transdermal patch is applied transdermally, on the one hand, the cumulative flux per unit area of the active ingredient is increased, and the rate and degree of drug delivery of the API are better; on the other hand, S-ketamine can achieve a sustained release of more than 2 days or more than 3 days, and the target duration of sustained administration is increased.
- the S-ketamine transdermal patch provided by the present invention has the following advantages: 1 The transdermal composition is administered through the skin, there is no sudden release of drug, and the safety risk of neurotoxic side effects is reduced, and there is no first-pass elimination in the liver after skin administration; 2 S-ketamine exists in a dissolved state in the skeleton material for a long time, no crystal precipitation occurs, and the composition has good stability; 3 The transdermal composition has good compatibility with the skin, is non-irritating, has good adhesion performance, is easy to use, and has high patient compliance; 4 After the transdermal composition is administered through the skin, it takes effect quickly, has good efficacy, and can significantly relieve depressive symptoms.
- FIG1 is a diagram showing the cumulative permeation per unit area of an S-ketamine transdermal patch with different thicknesses provided by the present invention
- FIG2 is a diagram showing the transdermal diffusion rate per unit area of an S-ketamine transdermal patch with different thicknesses provided by the present invention
- FIG3 is a crystallization diagram of an S-ketamine transdermal patch provided by the present invention after storage for 6 months; wherein A is a 10-fold imaging, and B is a 40-fold imaging;
- FIG4 is a drug concentration-time curve of an S-ketamine transdermal patch provided by the present invention in Bama miniature pigs;
- FIG5 is a comparison curve of the cumulative permeation per unit area of an S-ketamine transdermal patch provided by the present invention and the S-ketamine transdermal patches provided by Comparative Examples 1 and 2 in an in vitro diffusion experiment;
- FIG6 is a comparison curve of transdermal diffusion per unit area of an S-ketamine transdermal patch provided by the present invention and the S-ketamine transdermal patches provided by Comparative Examples 1 and 2 in an in vitro diffusion experiment.
- the present invention discloses an S-ketamine transdermal composition, and a preparation method and application thereof.
- the embodiments of the present invention will be described in detail below. It should be noted that, in the absence of conflict, the embodiments and features in the embodiments in the present application can be combined with each other arbitrarily.
- Preparation method of preparations 1-8 S-ketamine and solvent (ethyl acetate) were placed in a beaker, and different combinations of penetration enhancers were added according to Table 1 (preparations 2-8), or no penetration enhancer was added (preparation 1). After the components were dissolved, a corresponding amount of acrylic pressure-sensitive adhesive was added, and the mixture was stirred until a uniform mixture was obtained.
- the obtained S-ketamine-containing composition was coated on a PET 4400B film and dried in an oven for about 20 minutes at a drying temperature of 70° C. After being taken out, it was laminated together with a backing layer of Scotchpak TM 9754 and punched out to obtain an S-ketamine transdermal patch.
- the transdermal permeation rate of the S-ketamine transdermal composition without any permeation enhancer is lower than that of the S-ketamine transdermal composition containing two permeation enhancers (preparations 2-8); among the combinations containing two permeation enhancers, the permeation rate of the combination of fatty acid and fatty acid ester (preparation 2) is significantly higher than that of the combinations of other types of permeation enhancers (preparations 3, 4, 5, 6); and for the selection of pressure-sensitive adhesives, the pressure-sensitive adhesive without functional group substitution (preparation 2) is better than the acrylate pressure-sensitive adhesive with hydroxyl or carboxyl substitution (preparation 7, 8) can provide higher percutaneous permeability. In general, the combination of non-functional substituted acrylic pressure-sensitive adhesives with fatty acids and fatty acid esters can provide the highest percutaneous permeability.
- the acrylic pressure-sensitive adhesive The solid content of 87-4098 is 42.0%.
- the preparation method of S-ketamine transdermal composition and transdermal patch comprises the following steps:
- the acrylic pressure-sensitive adhesive The solid content of 87-4098 is 42.0%.
- the preparation method of formulation 10 is different from that of formulation 9 in that the release film is Scotchpak TM 9709 and the backing layer is Scotchpak TM 9723.
- the acrylic pressure-sensitive adhesive The solid content of 87-4098 is 42.0%.
- the preparation method of formulation 11 is the same as that of formulation 9, except that the release film is Scotchpak TM 1022 and the backing layer is Scotchpak TM 9722.
- the acrylic pressure-sensitive adhesive The solid content of 87-4098 is 42.0%.
- the preparation method of Formulation 12 is different from that of Formulation 9 in that the release film is Scotchpak TM 9709 and the backing layer is Scotchpak TM 9722.
- the acrylic pressure-sensitive adhesive The solid content of 87-4098 is 42.0%.
- the preparation method of Preparation 13 is different from that of Preparation 9 in that the thickness of the drug-containing matrix layer is adjusted to 100 ⁇ m during coating.
- the acrylic pressure-sensitive adhesive The solid content of 87-4098 is 42.0%.
- the preparation method of preparation 14 is the same as that of preparation 13.
- the acrylic pressure-sensitive adhesive The solid content of 87-4098 is 42.0%.
- the preparation method of preparation 15 is the same as that of preparation 13.
- the acrylic pressure-sensitive adhesive The solid content of 87-4098 is 42.0%.
- the preparation method of preparation 16 is the same as that of preparation 13.
- the prescription and preparation method of Preparation 13 were used to adjust the thickness of the drug-containing matrix layer to 50 ⁇ m, 75 ⁇ m, 100 ⁇ m, 125 ⁇ m and 150 ⁇ m. Three groups of parallel samples were set for each thickness of patch for transdermal diffusion experiment.
- transdermal diffusion experiments were set up for transdermal diffusion experiments: the prepared transdermal patches were removed from the release film layer and pasted on the surface of pig skin, and lightly pressed with fingers to ensure good adhesion between pig skin and patches. Then the pig skin was pasted between the Franz diffusion cell equipped with a rotor and the supply chamber, and the backing layer was in contact with the air and fixed with an iron clamp; 9 mL of pH 4.5 phosphate buffer was measured with a pipette and injected into the receiving chamber as the receiving medium, and a magnetic stirrer was added to stir at a constant temperature (32 ⁇ 0.5°C) and a constant speed (180r/min).
- the diffusion data of different thickness sample patches in vitro are shown in Figures 1 and 2.
- the thickness of the patch of the present invention is related to the duration of action, and increasing the thickness of the patch can extend the duration of the patch action.
- Patches with a thickness of 50 ⁇ m and 75 ⁇ m reach the drug release plateau at 52 h; patches with a thickness of 100 ⁇ m and 125 ⁇ m can achieve a sustained release of 72 h; patches with a thickness of 150 ⁇ m can achieve a sustained release effect of more than 72 h.
- the patch of the present invention can provide a slow release of drugs for more than 2 days or more than 3 days.
- Skin reaction grades include:
- Grade 4 erythema, blistering, and bullae formation
- Grade 3 erythema, blistering, no bullae
- Grade 2 erythema covers the entire patch area without blistering
- Grade 1 mild erythema covering less than the entire patch area
- Grade 0 minimal or no reaction at the patch site
- the samples prepared from Preparation 13 were used to observe the long-term crystallization of the S-ketamine transdermal patch of the present invention to confirm whether S-ketamine crystals would be produced in the prescription.
- FIG3 The crystallization observation after the sample was stored for 6 months is shown in FIG3 (A is a 10x image under a polarizing microscope, and B is a 40x image). It was found that the S-ketamine transdermal patch prepared by the present invention did not produce crystals during the 6-month long-term storage.
- mice Four Bama miniature pigs were selected for the experiment, half of which were male and half were female. After 14 days of adaptive feeding, the animals were grouped: animals of similar weight were selected, and the animals were randomly divided into two groups according to gender segments using a computer system, with 2 animals of each gender in each group. After the grouping was completed, the experimental animals were numbered, and then each animal was given the S-ketamine transdermal patch of the preparation 13 of the present invention. Before administration, the animals used electric clippers to remove the hair on the back skin to expose the skin. The area was cleaned with water and dried before administration. All animals were administered with a complete patch, which was removed after 72 hours of application.
- Blood was collected from the animals before administration and at 2h, 4h, 8h, 16h, 24h, 36h, 48h, 60h, 72h, 74h, 78h, 96h, 120h, and 144h after administration.
- the LC-MS/MS method was used to detect the concentration of S-ketamine in the samples, and the pharmacokinetic parameters were calculated. Grouping, The numbers and dosages are shown in the following table.
- the pharmacokinetic parameters of S-ketamine in animal plasma after transdermal administration of S-ketamine of the present invention are shown in the following table, and the blood drug concentration-time curve of the experimental animals is shown in FIG4 .
- the S-ketamine transdermal patch of the present invention can maintain a stable blood drug concentration within 72 hours.
- Example 2b of patent CN113710238A and Example 3 of patent CN107847469A comparative examples 1 and 2 of the present invention were designed respectively, and the prescription compositions are as follows:
- acrylic pressure-sensitive adhesive The solid content of 87-4287 is 39%.
- the S-ketamine transdermal patch of Comparative Example 1 was prepared by the following method: S-ketamine base and solvent (ethyl acetate), as well as levulinic acid and methyl laurate were placed in a beaker. 87-4287, and then the mixture was stirred at a speed of up to 300 rpm until a uniform mixture was obtained (stirring time was about 60 min).
- the resulting coating composition containing S-ketamine was coated on a polyethylene terephthalate film and heated at room temperature. The dried film was dried for about 15 min at 40 °C and 15 min at 60 °C. The dried film was laminated with a polyethylene terephthalate backing layer to obtain a self-adhesive layer structure containing S-ketamine. Individual systems were then punched out of the self-adhesive layer structure containing S-ketamine and sealed into a pouch of primary packaging material.
- acrylic pressure-sensitive adhesive The solid content of 87-2677 is 38%.
- the S-ketamine transdermal patch of Comparative Example 2 was prepared by a method similar to that of the comparative document.
- transdermal patches of the preparation 13 of the present invention and the comparative examples 1 and 2, and set up 3 parallel experiments (n 3) for each group to conduct transdermal diffusion experiments: remove the release film layer of the prepared transdermal patch, stick it on the surface of pig skin, and press lightly with fingers to ensure good adhesion between pig skin and patch. Then stick the pig skin between the Franz diffusion cell equipped with a rotor and the supply chamber, the backing layer is in contact with the air, and fixed with an iron clamp; use a pipette to measure 9mL of pH4.5 phosphate buffer as the receiving medium and inject it into the receiving chamber, add a magnetic stirrer and stir at a constant temperature (32 ⁇ 0.5°C) and a constant speed (180r/min).
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了S-氯胺酮经皮组合物及其制备方法和应用。该经皮组合物包括S-氯胺酮或其药学上可接受的盐,无官能团取代的丙烯酸酯压敏粘合剂,以及包含脂肪酸和脂肪酸酯的渗透促进剂。当施用本发明的经皮组合物时,S-氯胺酮的单位面积累积通量增加,药物递送速率及程度好,而且活性成分能达到2天以上或3天以上的持续释放。此外,本发明的经皮组合物稳定性好,与皮肤相容性好,无刺激性,且粘附性能佳,使用方便,患者使用顺应性高,能满足工业化规模生产的需要。
Description
本申请要求2022年9月30日提交的、发明名称为“S-氯胺酮经皮组合物及其制备方法和应用”、申请号为202211216868.6的中国发明专利申请的优先权权益,该中国专利申请的全部内容通过引用并入本文。
本发明涉及药物制剂领域,特别涉及S-氯胺酮经皮组合物、S-氯胺酮透皮贴剂及其制备方法和应用。
氯胺酮作为苯环利啶(Pce)的衍生物,是一种高亲和、非竞争性的NMDA受体拮抗剂,能作为精神科药物治疗抑郁症供临床使用。目前临床使用的氯胺酮多为消旋体,包含两种对映体,即S-氯胺酮和R-氯胺酮。研究表明,S-氯胺酮对NMDA受体、阿片受体、M胆碱受体的亲和力比R-氯胺酮高约2-4倍,且临床应用中的易出现幻觉、梦境等副作用主要由R型异构体引起。因此,相较于消旋氯胺酮和R-氯胺酮而言,S-氯胺酮疗效更佳,致幻、成瘾等副作用更小。
S-氯胺酮的i.v.施用和鼻内递送面临相同的临床劣势,血药浓度在短时间内快速升高(高Tmax和高Cmax),易增加药物突释和神经毒副反应安全性风险,且需要多次施用以维持平稳的血药浓度,患者依从性较低。近年来,越来越多的S-氯胺酮透皮治疗系统被公开。中国申请CN202080029020.5(CN113710238A)和CN201680037543.8(CN107847469A)分别公开了多种S-氯胺酮和氯胺酮透皮治疗系统,经皮施予这些透皮治疗系统能使S-氯胺酮受控、延长、稳定的暴露于人,可以满足期望的延长药物吸收特性。
发明内容
本发明提供了一种S-氯胺酮经皮组合物,以及该经皮组合物的制备方法和应用。本发明提供的经皮组合物能提供尽可能高的活性成分通量,同时,该经皮组合物在使用2天-3天时间内药物能缓慢释放,具有持续的体外释放特性,在较长的时间期限内,体内血浆浓度对时间的关系曲线更稳定。本发明提供的S-氯胺酮经皮组合物对人体皮肤无刺激性,产品稳定性好;而且,不会因增加的S-氯胺酮给药剂量或增多的给药频次而可能带来滥用风险。
第一方面,本发明提供了一种S-氯胺酮经皮组合物,该经皮组合物包含S-氯胺酮或其药学上可接受的盐,以及压敏粘合剂和渗透促进剂;所述压敏粘合剂为无官能团取代的丙烯酸酯压敏粘合剂;所述渗透促进剂包含脂肪酸和脂肪酸酯。
本发明中,S-氯胺酮,具有式(I)所示的化学结构:
本发明的经皮组合物中,无论使用的是S-氯胺酮,还是S-氯胺酮药学上可接受的盐,在计算活性物质含量时,均以S-氯胺酮的含量来进行计算。
本发明中含量为重量百分比。本发明所采用的压敏粘合剂通常为具有一定丙烯酸酯压敏粘合剂固含量的湿胶,因此丙烯酸酯压敏粘合剂的含量以其固含物重量计算。
在本发明的某一些实施方案中,基于所述经皮组合物的总重量,以重量百分数计,所述S-氯胺酮的含量为10%-20%。在另一实施方案中,所述S-氯胺酮的含量为10%-18%或11%-20%。在又一实施方案中,所述S-氯胺酮的含量为10%-15%、11%-18%或13%-20%。在又一实施方案中,所述S-氯胺酮的含量为10%-13%、11%-15%或13%-18%。在又一实施方案中,所述S-氯胺酮的含量为10%-11%、11%-13%或13%-15%。还在一实施方案中,所述S-氯胺酮的含量为10%、11%、12%、13%、14%、15%、16%、17%或19%。
在本发明的某一些实施方案中,基于经皮组合物的总重量,所述压敏粘合剂的含量为30%-75%。在另一实施方案中,所述压敏粘合剂的含量为30%-60%或45%-75%。在又一实施方案中,所述压敏粘合剂的含量为45%-60%或60%-75%。还在一实施方案中,所述压敏粘合剂的含量为53%、54%、55%、56%、57%、58%、59%、60%或61%。
在本发明的某一些实施方案中,所述无官能团取代的丙烯酸酯压敏粘合剂选自87-4098(以乙酸乙酯为溶剂,固含量为38.5%,含有乙酸乙烯酯,粘度为6500cP的无官能团取代的丙烯酸酯共聚物)、87-900A(以乙酸乙酯为溶剂,固含量为43%,不含乙酸乙烯酯,粘度为1800cP的无官能团取代的丙烯酸酯共聚物)、87-9301(以乙酸乙酯为溶剂,固含量为36.5%,不含乙酸乙烯酯,粘度为9500cP的无官能团取代的丙烯酸酯共聚物)、GMS 3083(以乙酸乙酯为溶剂,固含量为38%,不含乙酸乙烯酯,粘度为8500cP的无官能团取代的丙烯酸酯共聚物)、GMS 3253(以乙酸乙酯为溶剂,固含量为38.5%,不含乙酸乙烯酯,粘度为15000cP的无官能团取代的丙烯酸酯共聚物)中的一种或多种。
在一些实施方案中,所述无官能团取代的丙烯酸酯压敏粘合选自87-4098。
在本发明的某一些实施方案中,基于经皮组合物的总重量,所述渗透促进剂的含量为5%-40%。在另一实施方案中,所述渗透促进剂的含量为5%-35%或8%-40%。在另一实施方案中,所述渗透促进剂的含量为5%-30%、8%-35%或10%-40。在另一实施方案中,所述渗透促进剂的含量为5%-25%、8%-30%、10%-35%或15%-40。在另一实施方案中,所述渗透促进剂的含量为5%-15%、8%-25%、10%-30%、15%-35%或25%-40%。在另一实施方案中,所述渗透促进剂的含量为8%-15%、10%-25%、15%-30%或25%-35%。在又一实施方案中,所述渗透促进剂的含量为15%-25%。还在一实施方案中,所述渗透促进剂的含量为17%、18%、19%、20%、21%、22%或23%。
在本发明的某一些实施方案中,所述压敏粘合剂与所述渗透促进剂的重量比为
(1:1)-(5:1)。在另一实施方案中,所述压敏粘合剂与所述渗透促进剂的重量比为(1:1)-(4:1)或(2:1)-(5:1)。在又一实施方案中,所述压敏粘合剂与所述渗透促进剂的重量比为(1:1)-(3:1)、(2:1)-(4:1)或(3:1)-(5:1)。还在一实施方案中,所述压敏粘合剂与所述渗透促进剂的重量比为2:1、3:1或4:1。
在本发明的某一些实施方案中,所述渗透促进剂包含脂肪酸和脂肪酸酯。在本发明的某一些实施方案中,所述渗透促进剂由脂肪酸和脂肪酸酯组成。
在本发明的某一些实施方案中,基于所述经皮组合物的总重量,所述脂肪酸的含量为5%-35%。在另一实施方案中,所述脂肪酸的含量为5%-25%或10%-30%。在另一实施方案中,所述脂肪酸的含量为5%-20%、10%-25%或15%-30%。在另一实施方案中,所述脂肪酸的含量为5%-15%、10%-20%、15%-25%或20%-30%。在又一实施方案中,所述脂肪酸的含量为10%-20%、15%-20%或20%-25%。还在一实施方案中,所述脂肪酸的含量为17%、18%、19%、20%、21%、22%或23%。
在本发明的某一些实施方案中,基于所述经皮组合物的总重量,所述脂肪酸酯的含量为1%-10%。在另一实施方案中,所述脂肪酸酯的含量为1%-8%或3%-10%。在又一实施方案中,所述脂肪酸酯的含量为1%-5%、3%-8%或5%-10%。还在一实施方案中,所述脂肪酸酯的含量为1%、2%、3%、4%或5%。
在本发明的某一些实施方案中,所述脂肪酸与脂肪酸酯的重量比为(1:1)-(7:1)。在另一实施方案中,所述脂肪酸与脂肪酸酯的重量比为(1:1)-(6:1)或(2:1)-(7:1)。在另一实施方案中,所述脂肪酸与脂肪酸酯的重量比为(2:1)-(6:1)或(3:1)-(7:1)。在另一实施方案中,所述脂肪酸与脂肪酸酯的重量比为(3:1)-(6:1)或(4:1)-(7:1)。在另一实施方案中,所述脂肪酸与脂肪酸酯的重量比为(4:1)-(6:1)或(5:1)-(7:1)。在又一实施方案中,所述脂肪酸与脂肪酸酯的重量比为(5:1)-(6:1)或(6:1)-(7:1)。还在一实施方案中,所述脂肪酸与脂肪酸酯的重量比为5:1、6:1或7:1。
在本发明的某一些实施方案中,所述脂肪酸选自乙酰丙酸、戊酸、己酸、辛酸、壬酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山萮酸、木蜡酸、3-甲基丁酸、新庚酸、新壬酸、异硬脂酸、油酸、棕榈油酸、亚麻酸、11-十八碳烯酸、岩芹酸、反油酸、花生四烯酸、鳕油酸(gadoleic acid)、芥酸中的一种或多种。
在一些实施方案中,所述脂肪酸选自乙酰丙酸。
在本发明的某一些实施方案中,所述脂肪酸酯选自乳酸月桂酯、丙酸甲酯、戊酸甲酯、癸二酸二乙酯、月桂酸甲酯、月桂酸乙酯、月桂酸丙酯、油酸乙酯、油酸异丙酯、癸酸异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、丙二醇单辛酸酯、己二酸二异丙酯中的一种或多种。
在一些实施方案中,所述脂肪酸酯选自乳酸月桂酯。
在本发明的某一些实施方案中,所述S-氯胺酮经皮组合物还包含结晶抑制剂。
在本发明的某一些实施方案中,基于所述经皮组合物的总重量,所述结晶抑制剂的含量为5%-30%。在另一实施方案中,所述结晶抑制剂的含量为5%-20%或10%-30%。在另一实施方案中,所述结晶抑制剂的含量为5%-15%、10%-20%或15%-30%。在又一实施方案中,所述结晶抑制剂的含量为5%-10%、10%-15%或15%-20%。还在一实施方案中,所述结晶抑制剂的含量为10%、11%、12%、13%、14%或15%。
在本发明的某一实施方案中,所述S-氯胺酮与所述结晶抑制剂的重量比为(1:3)-(4:1)。
在另一实施方案中,所述S-氯胺酮与所述结晶抑制剂的重量比为(1:3)-(2:1)或(1:2)-(4:1)。在另一实施方案中,所述S-氯胺酮与所述结晶抑制剂的重量比为(1:3)-(1:1)、(1:2)-(2:1)或(1:1)-(4:1)。在又一实施方案中,所述S-氯胺酮与所述结晶抑制剂的重量比为(1:2)-(1:1)或(1:1)-(2:1)。还在一实施方案中,所述S-氯胺酮与所述结晶抑制剂的重量比为1:2、1:1、2:1或3:1。
在本发明的某一些实施方案中,所述结晶抑制剂选自聚甲基丙烯酸酯、聚乙烯吡咯烷酮聚合物、交联聚乙烯吡咯烷酮聚合物、聚乙烯吡咯烷酮共聚物、聚乙烯吡咯烷酮/乙酸乙烯酯共聚物、基于纤维素的聚合物、聚羧酸聚合物、聚乙二醇、聚醋酸乙烯酯和聚乙烯己内酰胺的接枝共聚物(PVAc-PVCap-PEG)中的一种或几种。
在一些实施方案中,所述结晶抑制剂选自聚甲基丙烯酸酯。在一些实施方案中,所述结晶抑制剂为B。
在一些实施方案中,所述S-氯胺酮经皮组合物包含S-氯胺酮、乙酰丙酸、乳酸月桂酯和87-4098;所述乙酰丙酸与乳酸月桂酯的重量比为(1:1)-(7:1),所述S-氯胺酮的含量为10%-20%,所述87-4098的含量为30%-75%。
在一些实施方案中,所述S-氯胺酮经皮组合物包含S-氯胺酮、乙酰丙酸、乳酸月桂酯、87-4098和B;所述乙酰丙酸与乳酸月桂酯的重量比为(1:1)-(7:1),所述S-氯胺酮与所述B的重量比为(1:3)-(4:1),所述S-氯胺酮的含量为10%-20%,所述87-4098的含量为30%-75%。
第二方面,本发明提供了一种S-氯胺酮透皮贴剂,该透皮贴剂包含背衬层、含药基质层和离型膜层,其中含药基质层包含上述S-氯胺酮经皮组合物。
在本发明的某一些实施方案中,所述含药基质层为骨架型结构。
在本发明的某一些实施方案中,所述含药基质层的厚度为50μm-150μm,在另一实施方案中,所述含药基质层的厚度为50μm、75μm、100μm、125μm或150μm。
在本发明的某一些实施方案中,该透皮贴剂的背衬层的材料选自聚乙烯-铝-聚酯/乙烯-乙酸乙烯复合膜、铝-聚酯膜、聚酯-聚乙烯复合膜、多层聚酯膜和聚酯-乙烯醋酸乙烯复合膜中的一种或多种。
在一些实施方案中,该透皮贴剂的背衬层的材料选自聚乙烯-铝-聚酯/乙烯-乙酸乙烯复合膜。
在本发明的某一些的实施方案中,该透皮贴剂的离型膜层的材料选自铝箔-硅脂复合物、硅化聚酯薄膜、氟聚合物涂覆聚酯薄膜、硅化铝箔和硅油纸中的一种或多种。
在一些实施方案中,该透皮贴剂的离型膜层的材料选自铝箔-硅脂复合物。
第三方面,本发明提供了前述S-氯胺酮透皮贴剂的制备方法,包括如下步骤:
(a)制备含药基质溶液;
(b)将含药基质溶液涂布于离型膜层,干燥,得到离型膜层与含药基质层的复合层;
(c)将背衬层复合于复合层的含药基质层上,得到透皮贴剂。
在一实施方案中,所述透皮贴剂的制备方法包括如下步骤:
(a)将结晶抑制剂与第一部分溶剂混合,得到结晶抑制剂储备溶液;
(b)将结晶抑制剂储备液与压敏粘合剂混合,得到空白基质溶液;
(c)将S-氯胺酮、渗透促进剂和剩余部分溶剂混合,得到S-氯胺酮储备液;
(d)将空白基质溶液和S-氯胺酮储备液混合,得到含药基质溶液;
(e)将含药基质溶液涂布于离型膜层,干燥,得到离型膜层与含药基质层的复合层;
(f)将背衬层复合于复合层的含药基质层上,得到透皮贴剂;
任选地,所述溶剂为乙酸乙酯或无水乙醇。
第四方面,本发明还提供了前述S-氯胺酮经皮组合物或前述S-氯胺酮透皮贴剂在制备用于治疗抑郁症的药物制剂中的用途。
在本发明的某一些实施方案中,所述抑郁症为成人难治性抑郁症或重度抑郁症。
在本发明所述制剂用途的另一实施方案中,所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂持续给药时长能达到24小时-96小时或以上。
在本发明所述制剂用途的另一实施方案中,所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂持续给药时长能达到24小时或以上。
在本发明所述制剂用途的另一实施方案中,所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂持续给药时长能达到48小时或以上。
在本发明所述制剂用途的另一实施方案中,所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂持续给药时长能达到72小时或以上。
在本发明所述制剂用途的另一实施方案中,所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂持续给药时长能达到96小时或以上。
在本发明所述制剂用途的一些实施方案中,每天一次、每两天一次、每三天一次、每四天一次或更长时间一次施用所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂。
第五方面,本发明还提供了一种治疗抑郁症的方法,所述的方法为对个体施用前述S-氯胺酮经皮组合物或透皮贴剂。
在本发明的某一实施方案中,所述抑郁症为成人难治性抑郁症或重度抑郁症。
在本发明所述治疗方法的某一实施方案中,所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂持续给药时长能达到24小时-96小时或以上。
在本发明所述治疗方法的某一实施方案中,所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂持续给药时长能达到24小时或以上。
在本发明所述治疗方法的某一实施方案中,所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂持续给药时长能达到48小时或以上。
在本发明所述治疗方法的某一实施方案中,所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂持续给药时长能达到72小时或以上。
在本发明所述治疗方法的某一实施方案中,所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂持续给药时长能达到96小时或以上。
在本发明所述治疗方法的某一实施方案中,每天一次、每两天一次、每三天一次、每四天一次或更长时间一次施用所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂。
相对于现有技术,本发明的有益效果如下:
(1)本发明中,无官能团取代的丙烯酸酯压敏粘合剂构成经皮组合物的骨架结构,当加入脂肪酸和脂肪酸酯作为该经皮组合物的渗透促进剂时,S-氯胺酮在骨架材料中的溶解性提高。当经皮肤施用S-氯胺酮透皮贴剂时,一方面,活性成分的单位面积累积通量增加,药物递送API的速率和程度更好;另一方面,S-氯胺酮可达到2天以上或3天以上的持续释放,持续给药目标时长增加。
(2)本发明提供的S-氯胺酮经皮贴剂,具有如下优点:①经皮组合物通过皮肤给药,无药物突释且神经毒副反应安全性风险降低,且皮肤给药无肝脏首过消除;②S-氯胺酮长期在骨架材料中以溶解状态存在,无结晶析出,组合物稳定性好;③该经皮组合物与皮肤相容性好,无刺激性,且粘附性能佳,使用方便,患者使用顺应性高;④该经皮组合物通过皮肤给药后,起效快,疗效好,能够明显缓解抑郁症状。
本申请的其它特征和优点将在随后的说明书中阐述,并且,部分地从说明书中变得明显,或者通过实施本申请而了解。本申请的其他优点可通过在说明书以及附图中所描述的方案来实现和获得。
附图概述
附图用来提供对本申请技术方案的理解,并且构成说明书的一部分,与本申请的实施例一起用于解释本申请的技术方案,并不构成对本申请技术方案的限制。
图1为本发明提供的一种S-氯胺酮透皮贴剂在具有不同厚度时的单位面积累积透过量;
图2为本发明提供的一种S-氯胺酮透皮贴剂在具有不同厚度时的单位面积透皮扩散率;
图3为本发明提供的一种S-氯胺酮透皮贴剂的存放6个月后的结晶图;其中A为10倍成像,B为40倍成像;
图4为本发明提供的一种S-氯胺酮透皮贴剂在巴马小型猪体内的药物浓度-时间曲线;
图5为本发明提供的一种S-氯胺酮透皮贴剂与对比例1、对比例2提供的S-氯胺酮透皮贴剂的体外扩散实验的单位面积累积透过量对比曲线;
图6为本发明提供的一种S-氯胺酮透皮贴剂与对比例1、对比例2提供的S-氯胺酮透皮贴剂的体外扩散实验的单位面积透皮扩散对比曲线。
详述
本发明公开了S-氯胺酮经皮组合物,及其制备方法和应用。为使本申请的目的、技术方案和优点更加清楚明白,下文中将对本发明的实施例进行详细说明。需要说明的是,在不冲突的情况下,本申请中的实施例及实施例中的特征可以相互任意组合。
仪器:HS-3垂直混合仪、C&D360涂布机/电热鼓风干燥箱、PL-3002-IC电子天平、KQ-500VDE超声波清洗机、MDC-25SX数显千分尺、XMTD-204恒温磁力搅拌器、Franz透皮扩散仪TK-24BL、GHP-9160恒温培养箱、WD-A药物稳定性检查仪。
实施例1
将制剂1-8的S-氯胺酮经皮组合物概括在下表中
表1制剂1-8的S-氯胺酮经皮组合物
制剂1-8的制备方法:在烧杯中装入S-氯胺酮和溶剂(乙酸乙酯),根据表1加入不同组合的渗透促进剂(制剂2-8),或不加任何渗透促进剂(制剂1),待组分溶解之后,加入对应含量的丙烯酸酯压敏粘合剂,继续搅拌该混合物直至得到均匀的混合物。
将得到的含S-氯胺酮的组合物涂覆在PET 4400B膜上,并于烘箱中干燥约20min,干燥温度为70℃。取出后与背衬层ScotchpakTM 9754一起层压,冲切后得到S-氯胺酮透皮贴剂。
皮肤渗透率的测定:
将制备好的透皮贴剂除去离型膜层,贴于猪皮表面,用手指轻压确保猪皮与贴剂粘附的良好性。然后将猪皮贴于装有转子的Franz扩散池和供给室之间,背衬层则与空气接触,并且用铁夹固定好;用移液管量取9mL pH4.5的磷酸盐缓冲液作为接收介质注入接收室中,加入磁力搅拌子在恒温(32±0.5℃)、恒速(180r/min)条件下搅拌。分别在0h、4h、8h、12h、16h、20h、24h、36h、48h、60h、72h时用1mL注射器取样0.8mL,同时补充同温等量的空白接收介质。取出的样品立即送往高效液相色谱仪器测定含量,基于72h的残留量和初始的S-氯胺酮含量计算S氯胺酮在72h时的渗透率,结果如下表所示:
表2 72h的S-氯胺酮经皮渗透率
由实施例1制得的经皮组合物的体外渗透效果可知:未加任何渗透促进剂的S-氯胺酮经皮组合物(制剂1),其经皮渗透率不及含有两种渗透促进剂的S-氯胺酮经皮组合物(制剂2-8);含有两种渗透促进剂的组合中,脂肪酸和脂肪酸酯(制剂2)组合的渗透率明显高于它们分别于其他种类的渗透促进剂组合(制剂3、4,制剂5、6);而对于压敏胶的选择,无官能团取代的压敏胶(制剂2)相较于羟基或羧基取代的丙烯酸酯压敏胶(制剂
7、8)能提供更高的经皮渗透率。总的来说,无官能团取代的丙烯酸酯压敏胶与脂肪酸、脂肪酸酯的组合能提供最高的经皮渗透率。
实施例2制剂9-制剂16的S-氯胺酮经皮组合物和透皮贴剂
制剂9
其中,所述丙烯酸酯压敏胶87-4098的固含量为42.0%。
S-氯胺酮经皮组合物及透皮贴剂的制备方法包括如下步骤:
(a)含药基质溶液制备:称取处方量的B于小瓶中,加入一定量乙酸乙酯溶解,得到B储备液,备用;另称取处方量的87-4098,与上述B储备液混合,得到空白基质溶液;将处方量的S-氯胺酮、乙酰丙酸和乳酸月桂酯加入一定量的乙酸乙酯混合,得到S-氯胺酮储备液;将上述S-氯胺酮储备液与上述空白基质溶液混合,得到含药基质溶液;
(b)涂布:将静置过夜后的含药基质溶液涂布于离型膜PET 4400B,调节涂布刀片的厚度至最终透皮贴剂含药基质层厚度为50μm;
(c)干燥:置于烘箱中,调节温度70℃,20min后取出,得到含药基质层与离型膜层的复合层;
(d)覆膜:将背衬层ScotchpakTM 9754复合于复合层的含药基质层上;
(e)冲切:冲切成面积为10cm2的圆形贴片,包装。
制剂10
其中,所述丙烯酸酯压敏胶87-4098的固含量为42.0%。
制剂10制备方法与制剂9的不同之处在于:离型膜选用ScotchpakTM 9709,背衬层选用ScotchpakTM 9723。
制剂11
其中,所述丙烯酸酯压敏胶87-4098的固含量为42.0%。
制剂11制备方法与制剂9相同,不同之处在于:离型膜选用ScotchpakTM 1022,背衬层选用ScotchpakTM 9722。
制剂12
其中,所述丙烯酸酯压敏胶87-4098的固含量为42.0%。
制剂12制备方法与制剂9的不同之处在于:离型膜选用ScotchpakTM 9709,背衬层选用ScotchpakTM9722。
制剂13
其中,所述丙烯酸酯压敏胶87-4098的固含量为42.0%。
制剂13制备方法与制剂9的不同之处在于:涂布时调节含药基质层厚度为100μm。
制剂14
其中,所述丙烯酸酯压敏胶87-4098的固含量为42.0%。
制剂14制备方法与制剂13相同。
制剂15
其中,所述丙烯酸酯压敏胶87-4098的固含量为42.0%。
制剂15制备方法与制剂13相同。
制剂16
其中,所述丙烯酸酯压敏胶87-4098的固含量为42.0%。
制剂16制备方法与制剂13相同。
实施例3涂布厚度筛选
1.方法
采用制剂13的处方和制备方法,调节含药基质层厚度为50μm、75μm、100μm、125μm和150μm,每种厚度贴剂分别设置3组平行样品进行透皮扩散实验。
2.透皮扩散试验
上述5种厚度的透皮贴剂,每组设置3组平行实验(n=3)进行透皮扩散实验:将制备好的透皮贴剂除去离型膜层,贴于猪皮表面,用手指轻压确保猪皮与贴剂粘附的良好性。然后将猪皮贴于装有转子的Franz扩散池和供给室之间,背衬层则与空气接触,并且用铁夹固定好;用移液管量取9mL pH4.5的磷酸盐缓冲液作为接收介质注入接收室中,加入磁力搅拌子在恒温(32±0.5℃)、恒速(180r/min)条件下搅拌。分别在0h、4h、8h、12h、16h、20h、24h、36h、48h、60h、72h时用1mL注射器取样0.8mL,同时补充同温等量的空白接收介质。取出的样品立即送往高效液相色谱仪器测定含量。体外透皮扩散结果如下表所示。
3.实验结果
表3不同厚度样品的单位面积累积透过量
表4不同厚度样品的单位面积透皮扩散率
具体地,不同厚度样品贴剂在体外的扩散数据如图1和图2所示,由图1和图2可知,本发明贴剂的厚度与作用时长相关,增加贴剂厚度可延长贴剂作用时长。厚度为50μm和75μm的贴剂在52h时到达药物释放平台期;厚度为100μm和125μm的贴剂可以实现72h缓释;厚度为150μm的贴剂可以实现72h以上的缓释效果。综上,本发明贴剂可以提供2天以上或3天以上的药物缓慢释放。
试验例1透皮贴剂皮肤反应测试
评价指标:
皮肤反应等级包括:
等级4:红斑,起泡和大疱形成;
等级3:红斑,起泡,无大疱;
等级2:红斑覆盖全部贴剂区域,没有起泡;
等级1:轻微红斑覆盖小于整个贴剂区域;
等级0:在贴剂部位最小或没有反应;
取本发明制剂9-16的样品各2份,分别贴于背部脱毛的大鼠24h,结果发现制剂9-16的贴剂在接触部位均没有皮肤刺激,皮肤反应测试等级为0。
试验例2透皮贴剂稳定性研究
以S-氯胺酮原料药为对照,测试制剂9-16的贴剂在常温、高温、加速条件及长期条件下的稳定性。各实验组条件设置情况如下表所示。
表5透皮贴剂稳定性研究样品试验条件
评价标准:最大未知单杂(%,≤0.5%),总杂(%,≤2.0%),稳定性研究结果如下表所示。
表6透皮贴剂稳定性研究结果
由上表可知,总体而言,在高温、加速以及长期条件下,本发明S-氯胺酮贴剂的储存比较稳定。
试验例3S-氯胺酮结晶研究
采用制剂13制备的样品,观察本发明S-氯胺酮透皮贴剂长期结晶情况,确认处方中是否会有S-氯胺酮结晶产生。
样品存放6个月后结晶观察情况如图3所示(A为偏光显微镜10倍成像,B为40倍成像),观测发现本发明制备的S-氯胺酮透皮贴剂在长期存放的6个月内未产生结晶。
试验例4巴马小型猪药代动力学研究
1.试验方法
试验选用巴马小型猪4只,雌雄各半。适应性饲养14天以后进行分组:选择体重相近的动物,使用计算机系统将动物按照性别区段随机分为2组,每组2只/性别动物,分组结束后对实验动物进行编号,随后每只动物给予本发明制剂13的S-氯胺酮透皮贴剂。动物于给药前使用电推剪去除背部皮肤被毛,暴露皮肤,给药前使用水清洗该部位并擦干,所有动物给药时均采用完整的贴剂进行贴敷,贴剂敷贴72h后揭去贴剂。动物于给药前,给药后2h、4h、8h、16h、24h、36h、48h、60h、72h、74h、78h、96h、120h、144h的时间点进行采血,采用LC-MS/MS方法检测样本中S-氯胺酮的浓度,计算药代参数。分组、
编号情况及给药剂量如下表所示。
表7药代动力学试验供试品剂量组分类
2.试验结果
本发明S-氯胺酮经皮肤给药后的动物血浆中S-氯胺酮药代动力学参数如下表所示,实验动物的血药浓度-时间曲线如图4所示。
表8动物血浆中S-氯胺酮药代动力学参数
根据图4可知,经皮给予本发明S-氯胺酮透皮贴剂后,各实验组小猪血药浓度在第8小时左右开始显著上升,从第8小时至第72小时,血药浓度一直维持稳定,72小时之后血药浓度开始下降。因此,本发明S-氯胺酮透皮贴剂可以维持72小时以内的稳定血药浓度。
对比例1与对比例2的S-氯胺酮经皮组合物
根据专利CN113710238A的实施例2b和专利CN107847469A的实施例3分别设计本发明对比例1、2,处方组成如下:
对比例1
其中,丙烯酸酯压敏胶87-4287的固含量为39%。
对比例1的S-氯胺酮透皮贴剂经如下方法制备:在烧杯中装入S-氯胺酮碱和溶剂(乙酸乙酯),以及乙酰丙酸和月桂酸甲酯。加入丙烯酸压敏粘合剂聚合物87-4287,然后将该混合物以至多300rpm的速度搅拌直至得到均匀的混合物(搅拌时间为约60min)。将所得的含S-氯胺酮的涂覆组合物涂覆在聚对苯二甲酸乙二醇酯薄膜上并在室温
下干燥约15min,在60℃下15min。将干燥的薄膜与聚对苯二甲酸乙二醇酯背衬层一起层压,得到含S-氯胺酮的自粘层结构。然后从含有S-氯胺酮的自粘层结构中冲压出单个系统,并密封到初级包装材料的小袋中。
对比例2
其中,丙烯酸酯压敏胶87-2677的固含量为38%。
参照对比文件相类似的方法制备对比例2的S-氯胺酮透皮贴剂。
本发明和对比例1、2的贴剂的皮肤渗透比较:
取本发明制剂13与对比例1、2的透皮贴剂,每组设置3组平行实验(n=3)进行透皮扩散实验:将制备好的透皮贴剂除去离型膜层,贴于猪皮表面,用手指轻压确保猪皮与贴剂粘附的良好性。然后将猪皮贴于装有转子的Franz扩散池和供给室之间,背衬层则与空气接触,并且用铁夹固定好;用移液管量9mL pH4.5的磷酸盐缓冲液作为接收介质注入接收室中,加入磁力搅拌子在恒温(32±0.5℃)、恒速(180r/min)条件下搅拌。分别在0h、4h、8h、12h、16h、20h、24h、36h、48h、60h、72h时用1mL注射器取样0.8mL,同时补充同温等量的空白接收介质。取出的样品立即送往高效液相色谱仪器测定含量。
三组样品的体外皮肤渗透比较结果如图5和图6所示。根据图示可知,本发明实施例透皮贴剂的单位面积透过量和单位面积透皮扩散率均优于对比例1、2所制得的透皮贴剂。
本申请描述了多个实施例,但是该描述是示例性的,而不是限制性的,并且对于本领域的普通技术人员来说明显的是,在本申请所描述的实施例包含的范围内可以有更多的实施例和实现方案。
Claims (34)
- 一种S-氯胺酮经皮组合物,包含S-氯胺酮或其药学上可接受的盐,以及药学上可接受的辅料,其中,所述药学上可接受的辅料包含无官能团取代的丙烯酸酯压敏粘合剂和渗透促进剂,所述渗透促进剂包含脂肪酸和脂肪酸酯。
- 根据权利要求1所述的S-氯胺酮经皮组合物,其中,基于所述经皮组合物的总重量,所述S-氯胺酮的含量为10%-20%。
- 根据权利要求1或2所述的S-氯胺酮经皮组合物,其中,所述压敏粘合剂与所述渗透促进剂的重量比为(1:1)-(5:1)。
- 根据权利要求1-3中任一项所述的S-氯胺酮经皮组合物,其中,基于经皮组合物的总重量,所述压敏粘合剂的含量为30%-75%;或者,所述渗透促进剂的含量为5%-40%。
- 根据权利要求1-4中任一项所述的S-氯胺酮经皮组合物,其中,所述压敏粘合剂选自87-4098、87-900A、87-9301、GMS 3083以及GMS 3253中的一种或多种。
- 根据权利要求1-5中任一项所述的S-氯胺酮经皮组合物,其中,所述压敏粘合剂为87-4098。
- 根据权利要求1-6中任一项所述的S-氯胺酮经皮组合物,其中,所述脂肪酸与所述脂肪酸酯的重量比为(1:1)-(7:1)。
- 根据权利要求1-7中任一项所述的S-氯胺酮经皮组合物,其中,所述脂肪酸选自乙酰丙酸、戊酸、己酸、辛酸、壬酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山萮酸、木蜡酸、3-甲基丁酸、新庚酸、新壬酸、异硬脂酸、油酸、棕榈油酸、亚麻酸、11-十八碳烯酸、岩芹酸、反油酸、花生四烯酸、鳕油酸、芥酸中的一种或多种。
- 根据权利要求1-8中任一项所述的S-氯胺酮经皮组合物,其中,所述脂肪酸为乙酰丙酸。
- 根据权利要求1-9中任一项所述的S-氯胺酮经皮组合物,其中,所述脂肪酸酯选自乳酸月桂酯、丙酸甲酯、戊酸甲酯、癸二酸二乙酯、月桂酸甲酯、月桂酸乙酯、月桂酸丙酯、油酸乙酯、油酸异丙酯、癸酸异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、丙二醇单辛酸酯、己二酸二异丙酯中的一种或多种。
- 根据权利要求1-10中任一项所述的S-氯胺酮经皮组合物,其中,所述脂肪酸酯为乳酸月桂酯。
- 根据权利要求1-11中任一项所述的S-氯胺酮经皮组合物,其中,所述药学上可接受的辅料还包含结晶抑制剂。
- 根据权利要求12所述的S-氯胺酮经皮组合物,其中,所述结晶抑制剂选自聚甲基丙烯酸酯、聚乙烯吡咯烷酮聚合物、交联聚乙烯吡咯烷酮聚合物、聚乙烯吡咯烷酮共聚物、聚乙烯吡咯烷酮/乙酸乙烯酯共聚物、基于纤维素的聚合物、聚羧酸聚合物、聚乙二醇、聚醋酸乙烯酯和聚乙烯己内酰胺基的接枝共聚物(PVAc-PVCap-PEG)及其组合。
- 根据权利要求12或13所述的S-氯胺酮经皮组合物,其中,所述结晶抑制剂为聚甲基丙烯酸酯。
- 根据权利要求12-14中任一项所述的S-氯胺酮经皮组合物,其中,所述结晶抑制 剂为B。
- 根据权利要求12-15中任一项所述的S-氯胺酮经皮组合物,其中,所述S-氯胺酮与所述结晶抑制剂的重量比为(1:3)-(4:1)。
- 根据权利要求12-16中任一项所述的S-氯胺酮经皮组合物,其中,基于所述经皮组合物的总重量,所述结晶抑制剂的含量为5%-30%。
- 根据权利要求1-11中任一项所述的S-氯胺酮经皮组合物,其中,所述S-氯胺酮经皮组合物包含S-氯胺酮、乙酰丙酸、乳酸月桂酯和87-4098;所述乙酰丙酸与乳酸月桂酯的重量比为(1:1)-(7:1),所述S-氯胺酮的含量为10%-20%,所述87-4098的含量为30%-75%。
- 根据权利要求12-17中任一项所述的S-氯胺酮经皮组合物,其中,所述S-氯胺酮经皮组合物包含S-氯胺酮、乙酰丙酸、乳酸月桂酯、87-4098和B;所述乙酰丙酸与乳酸月桂酯的重量比为(1:1)-(7:1),所述S-氯胺酮与所述B的重量比为(1:3)-(4:1),所述S-氯胺酮的含量为10%-20%,所述87-4098的含量为30%-75%。
- 一种S-氯胺酮透皮贴剂,包含背衬层、含药基质层和离型膜层,其中,所述含药基质层包含权利要求1-19中任一项所述的S-氯胺酮经皮组合物。
- 根据权利要求20所述的S-氯胺酮透皮贴剂,其中,所述含药基质层的厚度为50μm-150μm。
- 根据权利要求20或21所述的S-氯胺酮透皮贴剂,其中,所述背衬层为聚乙烯-铝-聚酯/乙烯-乙酸乙烯复合膜、铝-聚酯膜、聚酯-聚乙烯复合膜、多层聚酯膜和聚酯-乙烯醋酸乙烯复合膜中的一种或多种。
- 根据权利要求20-22中任一项所述的S-氯胺酮透皮贴剂,其中,所述背衬层为聚乙烯-铝-聚酯/乙烯-乙酸乙烯复合膜。
- 根据权利要求20-23中任一项所述的S-氯胺酮透皮贴剂,其中,所述离型膜层为铝箔-硅脂复合物、硅化聚酯薄膜、氟聚合物涂覆聚酯薄膜、硅化铝箔和硅油纸中的一种或多种。
- 根据权利要求20-24中任一项所述的S-氯胺酮透皮贴剂,其中,所述离型膜层为铝箔-硅脂复合物。
- 权利要求20-25中任一项所述的S-氯胺酮透皮贴剂的制备方法,其包括如下步骤:(a)制备含药基质溶液;(b)将所述含药基质溶液涂布于离型膜层,干燥,得到离型膜层与含药基质层的复合层;(c)将背衬层复合于所述复合层的所述含药基质层上,得到所述S-氯胺酮透皮贴剂。
- 权利要求1-19中任一项所述的S-氯胺酮经皮组合物或权利要求20-25中任一项所述的S-氯胺酮透皮贴剂在制备用于治疗抑郁症的药物制剂中的用途。
- 根据权利要求27所述的用途,其中,所述抑郁症为成人难治性抑郁症或重度抑郁症。
- 根据权利要求27或28所述的用途,其中,所述S-氯胺酮经皮组合物或所述S-氯 胺酮透皮贴剂持续给药时长能达到24小时-96小时或以上。
- 根据权利要求27-29中任一项所述的用途,其中,每天一次、每两天一次、每三天一次、每四天一次或更长时间一次施用所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂。
- 一种治疗抑郁症的方法,其包括对个体施用权利要求1-19中任一项所述的S-氯胺酮经皮组合物或权利要求20-25中任一项所述的S-氯胺酮透皮贴剂。
- 根据权利要求31所述的方法,其中,所述抑郁症为成人难治性抑郁症或重度抑郁症。
- 根据权利要求31或32所述的方法,其中,所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂持续给药时长能达到24小时-96小时或以上。
- 根据权利要求31-33中任一项所述的方法,其中,每天一次、每两天一次、每三天一次、每四天一次或更长时间一次施用所述S-氯胺酮经皮组合物或所述S-氯胺酮透皮贴剂。
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CN107847469A (zh) * | 2015-06-27 | 2018-03-27 | 美国神农制药责任有限公司 | 氯胺酮透皮递送系统 |
CN109966272A (zh) * | 2019-04-30 | 2019-07-05 | 深圳市泛谷药业股份有限公司 | 一种氯胺酮透皮贴剂及其制备方法 |
US20200030251A1 (en) * | 2017-04-20 | 2020-01-30 | Guangzhou Dazhou Biomedicine Ltd. | Transdermal drug delivery system for ketamine |
EP3725306A1 (en) * | 2019-04-17 | 2020-10-21 | LTS Lohmann Therapie-Systeme AG | Transdermal therapeutic system |
CN113710238A (zh) * | 2019-04-17 | 2021-11-26 | Lts勒曼治疗系统股份公司 | 透皮治疗系统 |
US20210393544A1 (en) * | 2020-06-19 | 2021-12-23 | Guangzhou Dazhou Biomedicine Ltd. | Transdermal drug delivery system for ketamine |
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CN107847469A (zh) * | 2015-06-27 | 2018-03-27 | 美国神农制药责任有限公司 | 氯胺酮透皮递送系统 |
US20200030251A1 (en) * | 2017-04-20 | 2020-01-30 | Guangzhou Dazhou Biomedicine Ltd. | Transdermal drug delivery system for ketamine |
CN110913844A (zh) * | 2017-04-20 | 2020-03-24 | 广州大洲生物医药科技有限公司 | 用于氯胺酮的透皮药物递送系统 |
EP3725306A1 (en) * | 2019-04-17 | 2020-10-21 | LTS Lohmann Therapie-Systeme AG | Transdermal therapeutic system |
CN113710238A (zh) * | 2019-04-17 | 2021-11-26 | Lts勒曼治疗系统股份公司 | 透皮治疗系统 |
CN109966272A (zh) * | 2019-04-30 | 2019-07-05 | 深圳市泛谷药业股份有限公司 | 一种氯胺酮透皮贴剂及其制备方法 |
US20210393544A1 (en) * | 2020-06-19 | 2021-12-23 | Guangzhou Dazhou Biomedicine Ltd. | Transdermal drug delivery system for ketamine |
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