US20120322781A1 - Pharmaceutical composition comprising 3-beta-hydroxy-5-alpha-pregnan-20-one with improved storage and solubility properties - Google Patents
Pharmaceutical composition comprising 3-beta-hydroxy-5-alpha-pregnan-20-one with improved storage and solubility properties Download PDFInfo
- Publication number
- US20120322781A1 US20120322781A1 US13/522,081 US201113522081A US2012322781A1 US 20120322781 A1 US20120322781 A1 US 20120322781A1 US 201113522081 A US201113522081 A US 201113522081A US 2012322781 A1 US2012322781 A1 US 2012322781A1
- Authority
- US
- United States
- Prior art keywords
- pharmaceutical composition
- beta
- oil
- pregnan
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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Images
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A—HUMAN NECESSITIES
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- 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
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Definitions
- the present invention relates generally to an improved formulation of 3-beta-hydroxy-5-alpha-pregnan-20-one.
- 3-beta-hydroxy-5-alpha-pregnan-20-one is a steroid in the pregnane family and a modulator of GABA A -receptor activity which is indicated for the treatment of sex/stress steroid induced disorders conditions (WO99/45931).
- 3-beta-hydroxy-5-alpha-pregnan-20-one is poorly soluble in many therapeutically acceptable solvents, which makes it difficult to administer the compound to a patient.
- Formulations with cyclodextrins are not suitable for administration to human patients.
- One reason for this is, because 3-beta-hydroxy-5-alpha-pregnan-20-one is poorly soluble, the formulation results in a large therapeutic volume that can only be administered intravenously.
- acylglycerol is meant all types and combinations of fatty acids esterified to glycerol.
- intermediate-chain acylglycerol is meant a mixture of acylglycerols where the total combined percentage of octanoic (caprylic) acid and decanoic (capric) acid is at least 95%.
- solid fat content is meant the percentage of solid as determined by pulse NMR (nuclear magnetic resonance).
- Root temperature denotes a temperature of between 18° C. and 25° C.
- U1010 denotes 3-beta-hydroxy-5-alpha-pregnan-20-one.
- Steprol or ester thereof denotes steroids with at least one hydroxyl group and esters of said steroids where at least one hydroxyl group has been used for the synthesis of an ester.
- Steroids such as sterols
- Steroids are usually described by the number of carbon atoms in the compound.
- cholesterol is a C27 sterol, which indicates that the compound consists of 27 carbon atoms.
- concentrations are stated as mg/g, that is, mg per gram of pharmaceutical composition.
- FIG. 1 shows mean plasma concentrations of 3-beta-hydroxy-5-alpha-pregnan-20-one (ng/mL) in rabbits following subcutaneous administration of 3-beta-hydroxy-5-alpha-pregnan-20-one in sesame oil with cholesterol (1:1) in two doses: 1 mg/kg (squares) and 5 mg/kg (circles).
- FIG. 2 shows 3-beta-hydroxy-5-alpha-pregnan-20-one concentration in filtrate (0.2 ⁇ m) from a suspension of 3-beta-hydroxy-5-alpha-pregnan-20-one in relation to cholesterol:3-beta-hydroxy-5-alpha-pregnan-20-one ratio.
- FIGS. 3 a , 3 b , 4 a and 4 b show photographs of suspensions of 3-beta-hydroxy-5-alpha-pregnan-20-one.
- An object of the present invention is to provide an improved formulation of 3-beta-hydroxy-5-alpha-pregnan-20-one in a pharmaceutically acceptable carrier.
- Another object of the present invention is to provide a formulation of 3-beta-hydroxy-5-alpha-pregnan-20-one with enhanced storage properties.
- Yet another object is to provide a formulation of 3-beta-hydroxy-5-alpha-pregnan-20-one with improved pharmacokinetics.
- Yet another object of the present invention is to provide a formulation of 3-beta-hydroxy-5-alpha-pregnan-20-one with increased solubility in a pharmacologically acceptable carrier.
- a first general aspect of the present invention which provides a pharmaceutical formulation comprising 3-beta-hydroxy-5-alpha-pregnan-20-one, at least one sterol or an ester thereof and a mixture of acylglycerols with a solid fat content of less than about 25% at 25° C. and about 0% at 37° C.
- a pharmaceutical composition obtainable according to a method according to the invention.
- a pharmaceutical composition for the treatment of conditions of the central nervous system In a fourth general aspect of the present invention there is provided use of a pharmaceutical composition for the treatment of conditions of the central nervous system.
- the inventors have found that the addition of a sterol surprisingly increases the solubility and improves the pharmacokinetics of 3-beta-hydroxy-5-alpha-pregnan-20-one in acylglycerols.
- the pharmaceutical composition comprises 3-beta-hydroxy-5-alpha-pregnan-20-one, at least one sterol or an ester thereof and a mixture of acylglycerols with a solid fat content of less than about 25% at 25° C. and about 0% at 37° C.
- a sterol with a hydroxyl group bound to the third carbon atom of the sterol structure is useful in the invention.
- the sterol may be cholesterol or beta-sitosterol, but also other sterols such as stigmasterol, brassicasterol or avenasterol may be used.
- cholesterol may be used.
- cholesteryl esters can be used.
- esters sodium cholesteryl sulphate, cholesteryl bensoate, cholesteryl acetate, cholesteryl caprylate, cholesteryl decanoate, cholestyl palmitate, cholesteryl oleate and cholesteryl stearate.
- the sterol or ester thereof can be a C18-C30 sterol or an ester thereof, a C21-C27 sterol or an ester thereof, or a C27-C29 sterol or ester thereof.
- the pharmaceutical composition can, in a first embodiment, be such that 3-beta-hydroxy-5-alpha-pregnan-20-one is essentially dissolved in the composition.
- 3-beta-hydroxy-5-alpha-pregnan-20-one can be dissolved or essentially dissolved according to this embodiment of the invention.
- the weight ratio of sterol (or ester thereof) to 3-beta-hydroxy-5-alpha-pregnan-20-one can, in this embodiment, be in the range of about 1:10 to 10:1.
- the sterol or ester thereof may be added in an amount that is similar to the amount of 3-beta-hydroxy-5-alpha-pregnan-20-one by weight. Because 3-beta-hydroxy-5-alpha-pregnan-20-one and a sterol have similar molecular weights this results in almost equimolar amounts of 3-beta-hydroxy-5-alpha-pregnan-20-one to sterol.
- the weight ratio of sterol to 3-beta-hydroxy-5-alpha-pregnan-20-one can be in the range of from 1:5 to 5:1.
- the weight ratio of sterol to 3-beta-hydroxy-5-alpha pregnan-20-one can be from 1:3 to 3:1.
- Suitable concentrations of 3-beta-hydroxy-5-alpha pregnan-20-one are between 0.1 mg/g and 75 mg/g.
- the concentration of 3-beta-hydroxy-5-alpha pregnan-20-one can also be between 1 mg/g and 50 mg/g, between 5 mg/g and 30 mg/g or between 10 mg/g and 25 mg/g.
- the pharmaceutical composition comprises a suspension of 3-beta-hydroxy-5-alpha-pregnan-20-one.
- the pharmaceutical composition will comprise 3-beta-hydroxy-5-alpha-pregnan-20-one in particles as well as 3-beta-hydroxy-5-alpha-pregnan-20-one dissolved in the composition.
- the sterol increases the soluble fraction of 3-beta-hydroxy-5-alpha-pregnan-20-one in such a suspension compared to a suspension without a sterol.
- One advantage with a suspension is that the formulation can contain a high concentration of 3-beta-hydroxy-5-alpha-pregnan-20-one.
- An additional advantage with a composition that comprises a suspension is that it results in slow release of 3-beta-hydroxy-5-alpha-pregnan-20-one.
- the particles are preferably of a range of sizes that is not engulfed by macrophages. Macrophages do primarily engulf particles of a size that is 2-3 micrometer (Champion et al, Pharm Res 2008; 25(8):1815-1821).
- the weight ratio of sterol (or ester thereof) to 3-beta-hydroxy-5-alpha pregnan-20-one can be in the range of about 1:10 to 10:1.
- the weight ratio of sterol to 3-beta-hydroxy-5alpha pregnan-20-one can be in the range of from 1:5 to 5:1.
- the weight ratio of sterol to 3-beta-hydroxy-5-alpha-pregnan-20-one can be from 1:4 to 3:1 or from 1:3 to 3:1.
- Suitable concentrations of 3-beta-hydroxy-5-alpha-pregnan-20-one are, in this second embodiment, between 0.1 mg/g and 750 mg/g.
- the concentration of 3-beta-hydroxy-5-alpha-pregnan-20-one can also be between 1 mg/g and 300 mg/g, between 1 mg/g and 100 mg/g, between 1 mg/g and 50 mg/g, between 5 mg/g and 30 mg/g or between 10 mg/g and 25 mg/g.
- the mixture of acylglycerols is characterized in that it has a solid fat content of less than about 25% at 25° C. and about 0% at 37° C.
- the solid fat content is, for practical purposes, 0% at 37° C.
- the solid fat content is at most 0.01% at 37° C.
- the mixture of acylglycerols can be a vegetable oil.
- it can be a vegetable oil selected from the group consisting of sesame oil, peanut oil, olive oil, and castor oil, or mixtures thereof.
- the mixture of acylglycerols can be a medium-chain acylglycerol, that is, a mixture of acylglycerols wherein the total combined percentage of fatty acids with 8 carbon atoms (octanoic acid) and 10 carbon atoms (decanoic acid) is at least 95%.
- the medium-chain acylglycerol can be various mixtures of monoacylglycerols, diacylglycerols and triacylglycerols.
- the medium-chain acylglycerol can consist of from about 50% to about 65% of monoacylglycerols, about 25% to about 35% of diacylglycerols, less than about 5% of triacylglycerols and less than about 2.5% of glycerol.
- An example of such a medium chain acylglycerol is Akoline MCM.
- the medium-chain acylglycerol can be such that it comprises at least about 95% triacylglycerols.
- Akomed R MCT is an example of such a medium-chain acylglycerol.
- the mixture of acylglycerols can comprise a mixture of a vegetable oil and a medium-chain acylglycerol.
- the mixture of acylglycerols can comprises a mixture of castor oil and a medium-chain acylglycerol where castor oil is present in an amount of between 40% and 60% by weight.
- the mixture of acylglycerols can consist of about 48% by weight of castor oil and about 52% by weight of a medium-chain acylglycerol.
- the mixture of acylglycerols can consist of about 48% by weight castor oil and about 52% by weight of a medium-chain acylglycerol.
- the pharmaceutical composition may comprise additional excipients known to a person skilled in the art such as antioxidants, preservatives, surfactants, coloring, flavoring, or thickening agents.
- the pharmaceutical composition can be administered to the patient by different means. Thus, it may be administered orally, parenterally or topically. Thus, the pharmacological composition may be administered subcutaneously, intramuscularly, intravenously, nasally, transdermally or vaginally.
- One method in which 3-beta-hydroxy-5-alpha-pregnan-20-one is dissolved or essentially dissolved in the composition, comprises the steps of a) dissolving 3-beta-hydroxy-5-alpha-pregnan-20-one in ethanol, b) adding a mixture of acylglycerols with a solid fat content of less than about 25% at 25° C. and about 0% at 37° C. and a sterol or ester thereof, c) mixing until a homogeneous liquid is obtained and d) evaporating the ethanol.
- the method may comprise a further step, which is the melting of the medium-chain acylglycerol before mixing it with the ethanol-drug preparation.
- the melting step enables the homogeneous mixing of this type of acylglycerol with other components. Once melted and mixed with the other components, the preparation remains in a liquid state for at least the time periods indicated in Table 1.
- the formulation comprises a suspension
- the formulation is advantageously prepared according to a method that comprises the following steps: 1) dissolving or suspending the sterol or ester thereof in the mixture of acylglycerols, 2) suspending 3-beta-hydroxy-5-alpha-pregnan-20-one in the acylglycerol-sterol mixture, 3) gently mixing.
- this procedure leads to suspended particles comprising 3-beta-hydroxy-5-alpha-pregnan-20-one of smaller size.
- compositions obtainable by the methods according to the second aspect of the invention.
- a fourth general aspect of the present invention there is provided the use of the pharmaceutical composition according to the invention for the treatment or prevention of conditions of the central nervous system.
- the pharmaceutical composition can be used to treat or prevent conditions of the central nervous system.
- conditions of the central nervous system examples include epilepsy, menstruation cycle dependant epilepsy, depression, stress related depression, migraine, tiredness and in particular stress related tiredness, premenstrual syndrome, premenstrual dysphoric disorder, menstrual cycle linked mood changes, stress related memory changes, menstrual cycle linked memory changes, Alzheimer's dementia, menstrual cycle linked difficulties in concentration, menstrual cycle linked sleep disorders and tiredness, substance abuse, menstrual cycle linked alcoholism, or combinations thereof.
- the pharmaceutical composition can be used to treat steroid induced mood disorders, in particular premenstrual dysphoric disorder.
- the pharmaceutical composition can also be used for treating or preventing side effects of oral contraceptives and postmenopausal therapy.
- the pharmaceutical composition can also be used for control or termination of steroid-induced anesthesia.
- 3-beta-hydroxy-5-alpha-pregnan-20-one was dissolved in various vehicles and was evaluated by eye for physical stability at room temperature over time. A formulation that did not undergo any visible changes in appearance and remained clear on storage in room temperature without signs of haziness, precipitation, sedimentation, phase separation into two or more liquid phases or change of colour, within 30 days was considered as “stable”.
- the desired amount of 3-beta-hydroxy-5-alpha-pregnan-20-one and sterol (for example cholesterol) was weighed in a 100 ml or 250 ml round-bottomed flask. To every gram of the mixture of 3-beta-hydroxy-5-alpha-pregnan-20-one and sterol a volume of about 30 ml of absolute ethanol was added. The mixture was treated in an ultrasonication bath (not exceeding 50° C.) until a clear liquid was obtained. This was normally accomplished within 10 minutes. The additional lipid ingredients indicated in the “Vehicle” column in Table 1 was then added up to 20 g. The resulting mixture was gently shaken by hand until a clear, homogeneous liquid was obtained. When the lipid was a solid at room temperature it was melted in the warm ultrasonication bath to a liquid form before addition.
- the alcohol was evaporated from the liquid on a rotary evaporator at a pressure of about 25 mbar and a temperature of about 40° C. until the weight of the flask was essentially constant.
- the remaining ethanol content was essentially less than 1%.
- the aim was to obtain a liquid with the appearance of clear oil at room temperature.
- the oily liquid was then transferred to clear glass vials and stored at room temperature until evaluation.
- the samples were evaluated by observing the samples in the glass vials and recording signs of haziness, precipitation, sedimentation, phase separation into two or more liquid phases, or change of colour after 1 or 2 days after preparation and after 30 days after preparation. In some cases, other time intervals were used (indicated in Table 1). Where indicated, the entire sample was placed in a refrigerator (2-8° C.) to provoke precipitation.
- 3-beta-hydroxy-5-alpha-pregnan-20-one (UC1010) (5 mg/g) and peanut oil was mixed into an emulsion with ethanol as described above in the concentrations shown in Table 1, and the ethanol was evaporated. The final weight of the preparation was 20 g. The mixture then had the form of an oily liquid. After one day when the sample was evaluated there were signs of precipitation. At 30 days the precipitate has formed a bottom sediment. Thus, the formulation was not stable.
- Example 2 was carried out essentially as Example 1 with the difference that cholesterol (5.5 mg/g) was added. When the sample was evaluated after one day the appearance of the sample had not changed. It was still unchanged after 30 days and after four months. After five months there was a slight precipitation.
- Example 2 compared with Example 1 shows how the addition of 5.5 mg/g cholesterol to a solution of 5 mg/g 3-beta-hydroxy-5-alpha-pregnan-20-one in peanut oil substantially increases the solubility so that, instead of precipitating, no precipitation occurred and the sample was stable for four months. However, a slight sedimentation occurred after 5 months.
- Examples 3 to 49 were carried out essentially as described above with the variations with regard to 3-beta-hydroxy-5-alpha-pregnan-20-one concentration, acylglycerol mixture used, sterol used and sterol concentration that are shown in Table
- Weighted amount of UC 1010 is the amount of 3-beta-hydroxy-5-alpha-pregnan-20-one per gram of final total composition including sterol (when a sterol is present).
- Vehicle denotes the carrier being tested.
- the amount of sterol is stated as “mg/g”, that is, the weight of sterol per weight of final total composition, including 3-beta-hydroxy-5-alpha-pregnan-20-one.
- “Appearance at preparation” describes the change of appearance of the mixture during preparation; usually the preparation is initially an emulsion or a solution whereas it has an oily appearance after evaporation of the ethanol; “Unchanged” denotes a sample that was stable and where thus 3-beta-hydroxy-5-alpha-pregnan-20-one remained in solution, without visible signs of haziness, precipitation, sedimentation, phase separation into two or more liquid phases or change of colour. This is also indicated by an asterisk (*) in the table.
- Examples 50 to 75 were carried out essentially as examples 1-49.
- Akoline Medium-Chain Monoglyceride (MCM) (Batch 8192270 and 8218940) and Akomed R Medium-Chain Triglyceride (MCT) (Batch 4765) were obtained from AarhusKarlshamns Sweden AB, Karlshamn, Sweden. Absolute ethanol (>99%) was obtained from VWR International.
- the procedure for making and evaluating lipid-based formulations was as follows: The batch sizes were either 20 g or 100 g of final formulation. The desired amounts of 3-beta-hydroxy-5-alpha-pregnan-20-one and cholesterol were weighed in a round-bottomed flask, 250 or 1000 ml depending on the batch size.
- the evaporation time was 0.5-1.5 h, depending on the batch size. The aim was to obtain a practically uncolored liquid with the appearance of a clear oil at room temperature. The liquid was transferred to clear glass vials, which were stored at room temperature until evaluation. Some selected formulations were portioned and stored at 2-8° C. for limited period of time.
- the evaluation comprised observation of the physical stability at room temperature over time. The samples were observed for haziness, precipitation of particles, aggregates or crystals, and subsequent sedimentation and/or phase separation into two or more liquid phases, and/or change of colour.
- the objective of the study was to investigate the comparative pharmacokinetics in plasma of a 3-beta-hydroxy-5-alpha-pregnan-20-one formulation comprising sesame oil and cholesterol following subcutaneous administration to New Zealand White rabbits.
- Two groups of three female rabbits each received single doses 1 mg/kg (formulation as in example 7) or 5 mg/kg (formulation as in example 10).
- blood samples were taken at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose.
- Concentrations of 3-beta-hydroxy-5-alpha-pregnan-20-one in plasma were measured by a validated LC-MS/MS method. Data are presented in FIG. 1 , and show mean plasma concentration (ng/mL) of 3-beta-hydroxy-5-alpha-pregnan-20-one for the two doses: 1 mg/kg (squares) and 5 mg/kg (circles).
- Suspensions of 3-beta-hydroxy-5-alpha-pregnan-20-one were prepared for investigation of solubility as follows: cholesterol was first dissolved at room temperature in sesame oil at 10 and 20 mg/ml, respectively. Suspensions of 3-beta-hydroxy-5-alpha-pregnan-20-one in sesame oil with different amounts of cholesterol were prepared on a magnetic stirrer at about 500 rpm using a conventional Teflon coated stir bar, at room temperature for several days, with occasional cycling to 2-8° C. At this time, the particles have become substantially smaller. Thereafter, samples of the respective suspensions were filtered through a 0.2 ⁇ m filter and analyzed with regard to concentration of 3-beta-hydroxy-5-alpha-pregnan-20-one.
- FIG. 2 shows data for a 3-beta-hydroxy-5-alpha-pregnan-20-one concentration of 10 mg/g.
- FIGS. 3 a and 3 b show microscopy pictures taken at 5 ⁇ enlargement of suspensions with a 3-beta-hydroxy-5-alpha-pregnan-20-one concentration of 10 mg/g and a cholesterol:3-beta-hydroxy-5-alpha-pregnan-20-one ratio of 1:1 immediately upon mixing (3a) and after several days of stirring (3b).
- Micronized 3-beta-hydroxy-5-alpha-pregnan-20-one (10 mg/g) with a mean particle size of 6 micrometer was suspended in sesame oil with cholesterol (20 mg/g) and stirred as in example 77. Photos were taken immediately upon suspension ( FIG. 4 a ) and after 19 hours of stirring ( FIG. 4 b ).
- a sterol such as cholesterol improves the possibilities to formulate 3-beta-hydroxy-5-alpha-pregnan-20-one in a pharmaceutical composition comprising acylglycerols, either as an oily solution or an oily suspension.
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US14/626,490 Active US9687496B2 (en) | 2010-01-14 | 2015-02-19 | Pharmaceutical composition comprising 3-beta-hydroxy-5-alpha-pregnan-20-one with improved storage and solubility properties |
US15/601,214 Active US11534446B2 (en) | 2010-01-14 | 2017-05-22 | Pharmaceutical composition comprising 3-beta-hydroxy-5-alpha-pregnan-20-one with improved storage and solubility properties |
US18/056,475 Pending US20230117905A1 (en) | 2010-01-14 | 2022-11-17 | Pharmaceutical composition comprising 3-beta-hydroxy-5-alpha-pregnan-20-one with improved storage and solubility properties |
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US15/601,214 Active US11534446B2 (en) | 2010-01-14 | 2017-05-22 | Pharmaceutical composition comprising 3-beta-hydroxy-5-alpha-pregnan-20-one with improved storage and solubility properties |
US18/056,475 Pending US20230117905A1 (en) | 2010-01-14 | 2022-11-17 | Pharmaceutical composition comprising 3-beta-hydroxy-5-alpha-pregnan-20-one with improved storage and solubility properties |
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US (4) | US20120322781A1 (zh) |
EP (1) | EP2523666B8 (zh) |
JP (1) | JP5687287B2 (zh) |
CN (1) | CN102753181B (zh) |
AU (1) | AU2011205821B2 (zh) |
BR (1) | BR112012017136B1 (zh) |
CA (1) | CA2786330C (zh) |
DK (1) | DK2523666T3 (zh) |
ES (1) | ES2566765T3 (zh) |
HU (1) | HUE027298T2 (zh) |
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PL (1) | PL2523666T3 (zh) |
RU (1) | RU2012133627A (zh) |
WO (1) | WO2011087441A1 (zh) |
ZA (1) | ZA201204574B (zh) |
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WO2013043985A1 (en) * | 2011-09-23 | 2013-03-28 | The Regents Of The University Of California | Edible oils to enhance delivery of orally administered steroids |
CN106146597A (zh) * | 2016-07-05 | 2016-11-23 | 浙江海洋大学 | 一种马尾藻甾醇化合物及其提取方法、应用 |
CN106146596A (zh) * | 2016-07-05 | 2016-11-23 | 浙江海洋大学 | 一种铜藻β‑谷甾醇化合物及其提取方法、应用 |
WO2018059241A1 (zh) * | 2016-09-27 | 2018-04-05 | 广西久福生物科技有限公司 | 一种具有戒毒药效的提取物及其制备方法 |
JP7278949B2 (ja) | 2017-01-09 | 2023-05-22 | アサリナ ファーマ アーベー | 注射可能な懸濁液 |
AU2018218823B2 (en) | 2017-02-10 | 2022-12-22 | Asarina Pharma Ab | 3-beta-hydroxy-5-alpha-pregnan-20-one for use in medical treatment |
BR112020010519A2 (pt) | 2017-11-27 | 2020-10-20 | Umecrine Cognition Ab | formulação farmacêutica de oxima de 3¿lfa-etinil-3¿eta-hidroxiandrostan-17-ona |
WO2020011789A1 (en) | 2018-07-09 | 2020-01-16 | Asarina Pharma Ab | Injectable suspensions |
EP3593789A1 (fr) * | 2018-07-11 | 2020-01-15 | Beta Innov | Composition contenant un dérivé de 7beta-hydroxycholestérol et un véhicule lipidique, et son utilisation dans le traitement de pathologies néoplasiques |
US20220202832A1 (en) * | 2019-04-05 | 2022-06-30 | The Regents Of The University Of California | Allopregnanolone compositions and uses thereof |
CN112341511A (zh) * | 2019-08-09 | 2021-02-09 | 南京诺瑞特医药科技有限公司 | 3-羟基-5-孕烷-20-酮衍生物及其用途 |
CN114907436A (zh) * | 2021-02-08 | 2022-08-16 | 南京诺瑞特医药科技有限公司 | 3-羟基-5-孕烷-20-酮衍生物的晶型及其制备方法和用途 |
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- 2011-01-14 CA CA2786330A patent/CA2786330C/en active Active
- 2011-01-14 PL PL11733156T patent/PL2523666T3/pl unknown
- 2011-01-14 CN CN201180005620.9A patent/CN102753181B/zh active Active
- 2011-01-14 JP JP2012548918A patent/JP5687287B2/ja active Active
- 2011-01-14 AU AU2011205821A patent/AU2011205821B2/en active Active
- 2011-01-14 EP EP11733156.1A patent/EP2523666B8/en active Active
- 2011-01-14 BR BR112012017136-4A patent/BR112012017136B1/pt active IP Right Grant
- 2011-01-14 US US13/522,081 patent/US20120322781A1/en not_active Abandoned
- 2011-01-14 MX MX2012008257A patent/MX2012008257A/es active IP Right Grant
- 2011-01-14 WO PCT/SE2011/050036 patent/WO2011087441A1/en active Application Filing
- 2011-01-14 ES ES11733156.1T patent/ES2566765T3/es active Active
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2012
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Also Published As
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EP2523666A1 (en) | 2012-11-21 |
CN102753181B (zh) | 2014-09-17 |
AU2011205821A1 (en) | 2012-07-12 |
US20170258809A1 (en) | 2017-09-14 |
CA2786330C (en) | 2013-11-19 |
CN102753181A (zh) | 2012-10-24 |
RU2012133627A (ru) | 2014-04-20 |
HUE027298T2 (en) | 2016-10-28 |
EP2523666B8 (en) | 2016-04-06 |
EP2523666B1 (en) | 2016-01-13 |
PL2523666T3 (pl) | 2016-06-30 |
MX2012008257A (es) | 2012-11-21 |
JP2013517269A (ja) | 2013-05-16 |
US20230117905A1 (en) | 2023-04-20 |
ES2566765T3 (es) | 2016-04-15 |
WO2011087441A1 (en) | 2011-07-21 |
CA2786330A1 (en) | 2011-07-21 |
DK2523666T3 (en) | 2016-04-04 |
BR112012017136B1 (pt) | 2021-05-25 |
US9687496B2 (en) | 2017-06-27 |
ZA201204574B (en) | 2013-08-28 |
BR112012017136A2 (pt) | 2018-06-12 |
JP5687287B2 (ja) | 2015-03-18 |
EP2523666A4 (en) | 2013-07-03 |
AU2011205821B2 (en) | 2013-07-25 |
US11534446B2 (en) | 2022-12-27 |
US20150164914A1 (en) | 2015-06-18 |
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