EP3764989A1 - Composition de suspension liquide stable de fludrocortisone - Google Patents

Composition de suspension liquide stable de fludrocortisone

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Publication number
EP3764989A1
EP3764989A1 EP19713218.6A EP19713218A EP3764989A1 EP 3764989 A1 EP3764989 A1 EP 3764989A1 EP 19713218 A EP19713218 A EP 19713218A EP 3764989 A1 EP3764989 A1 EP 3764989A1
Authority
EP
European Patent Office
Prior art keywords
fludrocortisone
liquid suspension
stable liquid
suspension composition
parahydroxybenzoate
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.)
Withdrawn
Application number
EP19713218.6A
Other languages
German (de)
English (en)
Inventor
Kamlesh Patel
Sanjaykumar Patel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Syri Ltd
Original Assignee
Syri Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Syri Ltd filed Critical Syri Ltd
Publication of EP3764989A1 publication Critical patent/EP3764989A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/56—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
    • A61K31/573—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 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids

Definitions

  • the present invention contemplates a stable liquid suspension composition of fludrocortisone or pharmaceutically acceptable salts thereof.
  • the present invention contemplates more particularly a stable liquid composition of fludrocortisone or pharmaceutically acceptable salts thereof suitable for oral administration.
  • Fludrocortisone (9-a-fluorocortisol) A synthetic analog of aldosterone that acts on the kidney so as to conserve sodium and excrete potassium. This definition includes derivatives of fludrocortisone, such as fludrocortisone acetate (which goes by the brand name Florinef®. Fludrocortisone in the form of its acetate salt has the chemical name 9- fluoro- 1 1 b.17.21 -trihydroxypregn-4-ene-3.20-dione 2l-acetate; its molecular formula is C23H31F06, and its molecular weight is 422.493. The structural formula is shown below;
  • Fludrocortisone is prescribed for partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison's disease and for the treatment of salt-losing adrenogenital syndrome.
  • the usual dose is 0.1 mg of fludrocortisone acetate daily, although dosage ranging from 0.1 mg three times a week to 0.2 mg daily has been employed. In the event transient hypertension develops as a consequence of therapy, the dose should be reduced to 0.05 mg daily.
  • Fludrocortisone acetate is preferably administered in conjunction with cortisone (10 mg to 37.5 mg daily in divided doses) or hydrocortisone (10 mg to 30 mg daily in divided doses).
  • Fludrocortisone Products comprising fludrocortisone are marketed under the trade name FLORINEF ® .
  • Various tablet formulations of fludrocortisone have been approved for marketing, for instance, conventional compressed instant release (IR) tablets comprising 0.1 mg of active ingredient. These are administered once, twice or three times daily.
  • IR compressed instant release
  • preparing extemporaneous suspension may result in degradation of the active ingredients, if the active ingredient is sensitive to water or any other solvent exposure which may result in a decrease in concentration of the active ingredient in extemporaneous suspension and patient may get less dose compared to the prescribed one for effective treatment.
  • solvent vehicle which is usually water or a medium comprised mostly of water
  • water or the solvent medium is usually the reason for the instability.
  • the solvent medium such as water may lead todegradation of the active ingredient. This is a potential issue for fludrocortisone.
  • the present invention relates a stable liquid suspension composition
  • a stable liquid suspension composition comprising fludrocortisone present in the range from 0.001 mg/ml to 1 mg/ml, a vehicle for fludrocortisone or salts thereof, a suspending agent, an anti foaming agent, at least one preservative and one or more inactive excipients.
  • said stable liquid suspension composition comprises;
  • the stable liquid suspension composition comprises;
  • the stable liquid suspension is formulated in water or an aqueous medium including water.
  • One more aspect of the present invention is to provide process for preparing said stable liquid suspension composition comprising steps of;
  • step b) adding a suspending agent to the solution of step a) optionally with continuous stirring,
  • step d) adding sweetener to the solution produced in step c), optionally with continuous stirring,
  • step e dispersing fludrocortisone acetate in a mixture of vehicle and purified water, f) adding the dispersion produced in step e) in to the suspension produced in step d) to get an homogenous suspension, optionally with continuous stirring, g) adding buffering agent to the suspension produced in step f) to adjust the pH to from 3 to 5, and
  • continuous stirring may be employed in order to ensure good dissolution or suspension of the relevant component.
  • Stable liquid pharmaceutical composition of fludrocortisone is the invention as further described herein.
  • the invention provides a stable liquid suspension composition comprising fludrocortisone present in the range from about 0.001 mg/ml to 1 mg/ml.
  • the composition includes a vehicle for fludrocortisone, a suspending agent, an anti foaming agent, at least one preservative and one or more inactive excipients.
  • pharmaceutically-acceptable salts as used herein includes salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • Suitable pharmaceutically-acceptable acid addition salts of fludrocortisone may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids examples include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, alginic, b-hydroxybutyric, malonic, galact
  • composition refers to a system in which small solid particles are essentially uniformly dispersed in a liquid medium.
  • stable suspension describes a suspension that shows no separation after being stored for at least 1 week at ambient temperature.
  • pH of the composition should be from 3 to 5, preferably the pH is from 3.8 to 4.2, and ideally about 4.
  • the stable liquid suspension composition of the present invention is chemically and physically stable without any precipitation or crystallization. This was demonstrated in a stability study. Another benefit is that the composition overcame the problem of unpleasant taste.
  • a stable liquid suspension composition according to the present invention shows good stability and reproducibility even after long-term storage. This means that a liquid composition can be stored for a few days or a week or longer without significant degradation.
  • the stable liquid suspension composition of present invention even though being in the form of a suspension also offers an advantage of uniform dosing, physical stability. It also reduces the chances of medication error or over dosage.
  • the stable liquid suspension composition of the present invention, as described herein remains stable for longer period during stability studies performed at different temperature and humidity condition.
  • Fludrocortisone acetate is a synthetic adrenocortical steroid possessing very potent mineralcorticoid properties and high glucocorticoid activity. It is used for its mineralcorticoid effects. It is a white to pale yellow, odourless or almost odourless, crystalline powder. Practically insoluble in water; soluble 1 in 50 in alcohol, 1 in 50 in chloroform; slightly soluble in ether.
  • fludrocortisone to be used in the form of Fludrocortisone acetate As per one embodiment, fludrocortisone to be used in the form of Fludrocortisone acetate.
  • a stable liquid suspension composition comprises fludrocortisone present in the range fromO.OOl mg/ml to 1 mg/ml, a vehicle for fludrocortisone, a suspending agent, an anti foaming agent, at least one preservative and one or more inactive excipients.
  • the liquid suspension is a suspension in water or a mixture of water and a co-solvent.
  • the liquid suspension is a suspension in water.
  • the stable liquid suspensions of the invention remain stable and uniform when appropriate excipients are selected and are used at specific and effective concentrations.
  • One of the main excipients that plays role in stabilizing the pharmaceutical composition of present invention is suspending agent and vehicle for fludrocortisone or salts thereof.
  • an appropriate vehicle is required to disperse fludrocortisone acetate before preparing the final composition.
  • Many vehicles are unsuitable for producing compositions of fludorocortisone.
  • the inventors of the present invention tried many vehicles and surprisingly found that appropriate stability is observed when the vehicle is selected from one or more of: polyethylene glycol, glycerol and propylene glycol.
  • glycerol is used as a vehicle for dispersing fludrocortisone acetate.
  • the amount of the vehicle for dispersing fludrocortisone acetate is used in the range from 0.01 to 5% w/v, and is preferably in the range from 0.05 to 1% w/v.
  • the suspending agent can be selected from one or more of: xanthan gum, guar gum, tragacanth gum, veegum, HPMC (hydroxypropyl methylcellulose), microcrystalline cellulose, Avicel RC-591 (microcrystalline cellulose/ sodium carboxymethyl cellulose), Carbopol® (carboxy vinyl polymer), polyvinyl Pyrrolidone.
  • the suspending agent is cellulose based, in a preferred embodiment, HPMC (hydroxypropyl methylcellulose), microcrystalline cellulose or Avicel RC-591 (microcrystalline cellulose/ sodium carboxymethyl cellulose).
  • HPMC hydroxypropyl methylcellulose
  • the suspending agent is HPMC (hydroxypropyl methylcellulose) also known as hypromellose.
  • Hypromellose is a solid, and is a slightly off-white to beige powder in appearance and may be formed into granules. The compound forms colloids when dissolved in water. This non-toxic ingredient is combustible and can react vigorously with oxidising agents.
  • HPMC is available in different grades commercially based on the viscosity for the product measured at 2% in water at 20°C.
  • HPMC Different grades available are HPMC followed by K100 LV, K4M, K15M, K100M, E15 LV, E50 LV, E4M, F50 LV, F4M code.
  • HPMC with low viscosity grade are preferred, including HPMC K100LV, HPMCE4M, HPMC E50LV and HPMC E15LV.
  • the suspending agent is HPMC E4M.
  • the concentration of the suspending agent is also important. Thisimpacts the final stability and physical characteristic of composition.
  • the % of suspending agent is in the range from 0.1 to 10 % w/v, more prefearably in the range from 0.25 to 5 % w/v and most preferred is 0.5 to 2.5 % w/v.
  • a substance used to reduce foam formation in liquid dosage compositions is called anti foaming agents also called as Defoamer.
  • Anti foaming agents also called as Defoamer.
  • a defoamer or an anti-foaming agent is a chemical additive that reduces and hinders the formation of foam in industrial process liquids.
  • the terms anti-foam agent and defoamer are often used interchangeably.
  • a defoamer is insoluble in the foaming medium and has surface active properties.
  • An essential feature of a defoamer product is a low viscosity and a facility to spread rapidly on foamy surfaces. It has affinity to the air-liquid surface where it destabilizes the foam lamellas. This causes rupture of the air bubbles and breakdown of surface foam. Entrained air bubbles are agglomerated, and the larger bubbles rise to the surface of the bulk liquid more quickly.
  • the anti-foaming agent for the present invention can be selected from one or more of: polydimethylsiloxane, simethicone, other silicones, stearates, alcohols and glycols.
  • the anti -foaming agent may be of more than one of the above agents.
  • the anti foaming agent is simethicone.
  • the anti foaming agent is present in the range from 0.005 to 1 % w/v. In a preferred embodiment, anti foaming agent is present in the range from 0.01 to 0.5 % w/v. In a more preferred embodiment, anti foaming agent is present in the range from 0.01 to 0.1 % w/v. In a most embodiment, anti foaming agent is present in the range from 0.02 to 0.08 % w/v.
  • suitable preservative for present invention can be selected from one or more of: methyl parahydroxybenzoate (methyl paraben), ethyl parahydroxybenzoate (ethyl paraben), propyl parahydroxybenzoate (propyl paraben), butyl parahydroxybenzoate (butyl paraben), isobutyl parahydroxybenzoate (isobutyl paraben), isopropyl parahydroxybenzoate (isopropyl paraben), benzyl parahydroxybenzoate (benzyl paraben), Sodium Benzoate, Benzoic acid, Potassium Sorbate and combinations thereof.
  • the preservative is present in the range from about 0.001 %w/v to about 0.5 %w/v.
  • the present stable liquid suspension composition of present invention contains one or more inactive excipients selected from buffering agent, sweetener, anti oxidant, coloring agent and flavoring agent.
  • suitable buffer for present invention is selected from one or more of: Citric Acid monohydrate, Sodium Citrate, Sodium Dihydrogen Phosphate, Disodium Phosphate, Trometamol (Tris), Disodium hydrogen phosphate anhydrous, Hydrochloric Acid, Ascorbic Acid, Sodium Ascorbate and anhydrous, monohydrate or dehydrate forms thereof.
  • the buffer can be single or any combination of above listed buffer. In a preferred embodiment, combination of Disodium hydrogen phosphate anhydrous and Citric Acid monohydrate is to be used.
  • suitable sweetener for present invention is selected from one or more of: acesulfame potassium, sucralose, cyclamate, saccharin, saccharin sodium and aspartame or mixtures thereof.
  • sucralose is to be used.
  • the liquid pharmaceutical composition of the present invention can be prepared in absence of sweetener. However to make it more palatable and easily acceptable by patient especially children, very small amount of sweetener can be added. Sweetener for the present invention can be used in the range from about 0.01 %w/v to 0.5 % w/v.
  • the liquid pharmaceutical composition may further comprise anti oxidants.
  • Suitable antioxidants for the composition of the present invention can be selected from one or more of: consisting ofbutylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, alpha-tocopherol, propyl gallate, gentisic acid sodium ascorbate, sodium bisulfite, sodium metabisulfite, monothioglycero, cysteine, thioglycolate sodium, acetone sodium bisulfite, ascorbate (sodium/acid), bisulfite sodium, cystein/cysteinate HC1, dithionite sodium (Na hydrosulfite, Na sulfoxylate), gentisic acid, gentisic acid ethanolamine, glutamate monosodium, formaldehyde sulfoxylate sodium, metabisulfite potassium, metabisulfite sodium, monothioglycerol (thioglycerol), propyl gallate, sul
  • the vehicle or solvent for making the final volume of the composition can be selected from one or more of: glycerine, alcohols, propylene glycol, polyethylene glycol, purified water, ethanol and isopropyl alcohol.
  • the vehicle or solvent may include mixtures of the above agents Preferably purified water is used as a solvent.
  • said stable liquid suspension composition comprises;
  • the stable liquid composition of fludrocortisone is to be used for partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison's disease. It can also be used for the treatment of salt-losing adrenogenital syndrome.
  • said stable liquid suspension composition comprises;
  • a suspending agent selected from xanthan gum, guar gum, tragacanth gum, veegum, HPMC (hydroxypropyl methylcellulose), microcrystalline cellulose, Avicel RC-591 (microcrystalline cellulose/ sodium carboxymethyl cellulose), Carbopol® (carboxyvinyl polymer), polyvinyl Pyrrolidone, or mixtures thereof
  • an anti foaming agent selected from polydimethylsiloxane, simethicone, other silicones, stearates, alcohols, glycols or combinations thereof,
  • said stable liquid suspension composition comprises;
  • said stable liquid suspension composition comprises;
  • the stable liquid suspension composition is prepared by:
  • step b) adding suspending agent in step a) with continuous stirring
  • step b) adding antifoaming agent in step b) with continuous stirring
  • step d) adding sweetener to step c) with continuous stirring
  • step e) dispersing fludrocortisone acetate in mixture of vehicle and purified water, f) adding dispersion of step e) in to step d) with continuous stirring to get homogenous suspension,
  • step f) adding buffering agent to step f) to adjust pH to from 3 to 5 and
  • the stable liquid suspension composition is prepared by a) adding methyl parahydroxybenzoate (methyl paraben) and ethyl parahydroxybenzoate (ethyl paraben in water and stirring till dissolve it, b) adding HPMC (hydroxypropyl methylcellulose) E4M in step a) with continuous stirring,
  • step b) adding simethicone in step b) with continuous stirring
  • step d) adding sucralose to step c) with continuous stirring
  • step e) dispersing fludrocortisone acetate in mixture of glycerol and purified water, f) adding dispersion of step e) in to step d) with continuous stirring to get homogenous suspension,
  • step f) adding citric acid monohydrate and disodium hydrogen phosphate anhydrous to step f) to adjust pH in between 3 to 5 and
  • step 2 Add HPMC E4M in step 1 when temperature reaches 60-70°C and keep aside to cool at room temperature.
  • step 5 Add dispersion of step 5 into step 4 and mix to get homogeneous suspension.
  • Example 1 Make up to volume with purified water and stir for 10 minutes to get homogeneous suspension. Physical observations: The composition of Example 1 was observed after storing for 24 hrs at room temperature. No any sedimentation or colour change observed, hence further stability studies at different temperature/humidity and time duration was planned.
  • Example 2 Comparative examples
  • Example 2 The composition of Example 2 (2A, 2B and 2C) was observed after storing for 24 hrs at room temperature. There are sedimentation as well as slight color change was observed in all three composition. Therefore no further stability studies were conducted.
  • Example 3 The composition of Example 3 was observed after storing for 24 hrs at room temperature. There are very little sedimentation was observed but that was redisersible on shaking. No further stability conducted.
  • Example 4 Stability study of Example 1
  • Example 1 shows good stability for 6 months storage when stored in the condition of

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Abstract

La présente invention concerne une composition de suspension liquide stable appropriée pour une administration par voie orale comprenant de la fludrocortisone ou des sels pharmaceutiquement acceptables de celle-ci et un procédé de préparation de ladite composition pharmaceutique de suspension liquide.
EP19713218.6A 2018-03-12 2019-03-03 Composition de suspension liquide stable de fludrocortisone Withdrawn EP3764989A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1803893.5A GB2571937B (en) 2018-03-12 2018-03-12 Stable liquid suspension composition of fludrocortisone
PCT/IB2019/051696 WO2019175703A1 (fr) 2018-03-12 2019-03-03 Composition de suspension liquide stable de fludrocortisone

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EP3764989A1 true EP3764989A1 (fr) 2021-01-20

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EP (1) EP3764989A1 (fr)
GB (1) GB2571937B (fr)
WO (1) WO2019175703A1 (fr)

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CN111759814A (zh) * 2020-07-20 2020-10-13 华益药业科技(安徽)有限公司 一种用于抗炎的醋酸氟氢可的松片及加工工艺
CN111759812A (zh) * 2020-07-20 2020-10-13 华益药业科技(安徽)有限公司 一种抑制结蹄组织增生的醋酸氟氢可的松片及其加工工艺
JP2024529509A (ja) * 2021-07-30 2024-08-06 エピジェニクス セラピューティクス インコーポレーテッド クレミゾール製剤

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