WO2013182170A1 - Augmentation de la vitesse de dissolution d'une composition pharmaceutique comprenant de l'acétate de bazédoxifène - Google Patents

Augmentation de la vitesse de dissolution d'une composition pharmaceutique comprenant de l'acétate de bazédoxifène Download PDF

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Publication number
WO2013182170A1
WO2013182170A1 PCT/CZ2012/000048 CZ2012000048W WO2013182170A1 WO 2013182170 A1 WO2013182170 A1 WO 2013182170A1 CZ 2012000048 W CZ2012000048 W CZ 2012000048W WO 2013182170 A1 WO2013182170 A1 WO 2013182170A1
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Prior art keywords
bazedoxifene acetate
hydrophilic compound
process according
bazedoxifene
rpm
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Application number
PCT/CZ2012/000048
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English (en)
Inventor
Abid Riaz AHMED
Pawel STASIAK
Roman HAMTIL
Jaroslav Riha
Original Assignee
Zentiva, K. S.
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Priority to PCT/CZ2012/000048 priority Critical patent/WO2013182170A1/fr
Publication of WO2013182170A1 publication Critical patent/WO2013182170A1/fr

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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

  • the invention deals with a process for preparation of tablets comprising apeledoxefine acetate demonstrating enhanced dissolution rate.
  • Osteoporosis is a gender-related disease that is especially prevalent in postmenopausal women. Postmenopausal osteoporosis is an increasing worldwide health concern affecting an estimated 200 million individuals. The on-going need for new osteoporosis therapies has led to the development of new selective estrogen receptor modulators (SERMs) with an ideal tissue selectivity profile and beneficial effects on bone without undesirable effects on the endometrium and breast (Chines and Med, 2009).
  • SERMs selective estrogen receptor modulators
  • Bazedoxifene acetate (1-[4-(2-azepan-1 -yl-ethoxy)benzyl]-2-(4-hydroxyfenyl)-3-methyl-1 H- indol-5-ol acetic acid), having the chemical formula shown below, is a new, third-generation, oral, nonsteroidal, indole-based selective estrogen receptor modulator (SERM) being developed for the prevention and treatment of osteoporosis.
  • SERM selective estrogen receptor modulator
  • Bazedoxifene acetate form B is thermodynamically more stable than form A.
  • the polymorphic form A has higher solubility in aqueous and organic system than does form B. The higher solubility of polymorphic form A makes it potential candidate to prepare pharmaceutical formulations.
  • EP 2311805A 1 reports the Bazedoxifene acetate polymorphic form C which can be used in the preparation of pharmaceutical formulations.
  • PCT application WO0203987A2 describes oral formulations of one or more poorly soluble estrogenic compounds comprising a carrier or excipient systems of a filler and disintegrant component and a lubricant component, preferably with an antioxidant.
  • the formulations may be in any conventionally used oral forms (tablets, capsules, buccal forms, troches, lozenges, suspensions) and may be prepared by any conventional method without any closer specification (compression, wet granulation, dry granulation), with standard or delayed release of the API.
  • the only example of formulation without antioxidant (Example 1 ) was shown to be chemically unstable (Example 5).
  • Solid dispersion comprising acetate and methods of their preparation.
  • the solid dispersions are prepared by combining the apeledoxifene acetate either with a dispersing agent in solution and removing the solvent or with melted dispersing agent and solidifying the liquid mixture.
  • PCT application WO2007024961 describes oral formulations of apeledoxifene acetate polymorphic form A prepared by dry processes, preferably by direct mixing, comprising a carrier or excipient system that prevents or minimizes the polymorphic conversion of the active ingredient.
  • a carrier or excipient system that prevents or minimizes the polymorphic conversion of the active ingredient.
  • the usage of a surfactant was not recommended because it was believed to facilitate the polymorphic conversion of the API.
  • the formulations were prepared by the direct blending.
  • Solubility of apeledoxifene is pH-dependent and at pH below 5.0 is approx. 0.5 mg/ml ⁇ EMA Assessment Report for Conbriza, 2009).
  • Low solubility of apeledoxifene in water leads to technological issues in immediate release solid preparations. Following slow dissolution rate, rate of the drug absorption from gastrointestinal tract is limited. Therefore, preparation of solid drug forms demonstrating enhanced dissolution rate and allowing for fast absorption would be valuable for therapy with apeledoxifene.
  • the present invention relates to a process of preparation of a tablet for oral administration of adoxifene acetate with enhanced release of the active compound from the formulation.
  • the process of the invention comprises intensive intimate contacting the active compound apeledoxifene acetate with a hydrophilic compound. This is achieved either by intensive mixing of micronised apeledoxifene acetate with a hydrophilic compound, or by co-grinding of the apeledoxifene acetate together with a hydrophilic compound at a ratio 1 :0.5-1 :6. These pre-mixes are then used for preparation of solid formulations demonstrating enhanced dissolution rate, preferably by forming a rapidly disintegrating tablet core by method of direct compression, dry granulation or wet granulation.
  • the tablet core can be optionally coated with a protective polymeric film.
  • the present invention presents a process of preparation of tablets comprising apeledoxifene acetate with enhanced dissolution wherein the micronized active substance is intensively mixed or co-grinded with hydrophilic compounds.
  • the proper selection of excipients allows for rapid disintegration of the formulation and thus fast onset of apeledoxifene acetate dissolution.
  • Such a combination of the process and the suitable excipients was found which resulted in disintegration time of the tablet core not more than 5 minutes and at least 80% of apeledoxifene acetate was dissolved within 15 minutes (Fig. 1 ). This allows for high concentration of the active substance in stomach and its fast absorption to the blood circulation system.
  • the main aspect of the invention is a process for preparation of apeledoxifene acetate tablets, the process comprising a step of preparation of a pre-mix of apeledoxifene acetate with a hydrophilic compound by intensive intimate contacting apeledoxifene acetate with the hydrophilic compound. This is achieved either by intensive mixing of micronised apeledoxifene acetate with a hydrophilic compound, or by co-grinding of the apeledoxifene acetate together with a hydrophilic compound wherein the ratio of the apeledoxifene acetate to the hydrophilic compound is between 1 :0.5-1 :6.
  • These pre-mixes are blended with other pharmaceutically acceptable excipients and further processed by method of direct compression, dry granulation, wet granulation or their combination.
  • the pre-mix of apeledoxifene acetate with a hydrophilic compound can be prepared by intensive mixing of micronized apeledoxefine acetate with a hydrophilic compound.
  • the mixing can be performed in a high shear mixer for at least 60 seconds, preferably for 5-15 minutes, most preferably for 10 min, with the mixer speed 1200-2500 rpm and the chopper speed 1500-2500 rpm, preferably with the mixer speed 1500-1800 rpm and the chopper speed 1800-2000 rpm.
  • the mixing can be also performed in a turbula mixer for at least 10 minutes, preferably for 15 minutes, at 20-50 rpm, preferably at 30 rpm.
  • the pre-mix of apeledoxifene acetate with a hydrophilic compound can be prepared by co-grinding of the non-micronized apeledoxifene acetate together with a hydrophilic compound using a jet mill at 1-3 bar pressure, preferably at 3 bar, wherein the ratio of the apeledoxifene acetate to the hydrophilic compound is between 1 :0.5 and 1 :6, preferably between 1 :0.5 and 1 :3, still more preferably between 1 :0.5 and 1 : 1 and most preferably is 1 : 1.
  • the micronized apeledoxifene acetate in the pre-mix i.e.
  • the D 90 value is lies below 50 ⁇ , preferably between 5-20 ⁇ and more preferably between 10-15 ⁇
  • the D 90 shall be understood to mean that 90% of the particles having a particle size smaller than or equal to the indicated value as determined by conventional laser diffraction technique.
  • the polymorphic form C was used herein as the most preferred for its suitable physic-chemical properties.
  • any reference to apeledoxifene acetate is intended to include apeledoxifene acetate polymorphic form C, if not explicitly indicated to the contrary.
  • Polymorphic form C of Bazedoxifene acetate was selected and used because it was proved to exhibit the best combination of the physico-chemical properties that are advantageous for the pharmaceutical formulations compared to polymorphic forms A, B and amorphous form (Table 1 ).
  • the polymorphic form C of Bazedoxifene acetate together with form B is chemically more stable, has higher polymorphic stability and is less hygroscopic than form A and amorphous.
  • Hygroscopicity is the ability of a substance to attract and hold water molecules (e.g. atmospheric moisture) from the surrounding environment through either absorption or adsorption with the absorbing or adsorbing material becoming physically "changed". It is one of the indicators of the stability of active ingredients.
  • Hygroscopic substances need to be specifically stored (e.g. aluminium foil + desiccant) to remain unchanged.
  • Hygroscopicity of polymorphic form C of Bazedoxifene acetate is comparable with form B whereas form A sorbed significantly higher amount of water.
  • Hygroscopicity of amorphous form is immense.
  • the hydrophilic compounds comprise at least one hydrophilic filler, most preferably from the group of monosaccharaides or disaccharides or their derivatives, and optionally other hydrophilic compounds, e.g. such as surfactants, specified below.
  • the hydrophilic filler can be selected from those known in the art, including lactose (e.g.
  • anhydrous or monohydrate anhydrous or monohydrate
  • saccharose raffinose
  • compressible sugar commercially available combination of 95.0 to 98.0% sucrose and 2 to 5% dried glucose syrup or maltodextrin
  • glucose fructose
  • dextrose dextrose
  • sugar alcohols such as mannitol, sorbitol, maltitol, xylitol, lactitol, and mixtures thereof.
  • the preferred hydrophilic fillers are lactose and mannitol, more preferred is lactose, mostly lactose monohydrate. Additional excipients, such fillers, binders, disintegrants, surfactants, lubricants and glidants may be added to the pre-mixes of apeledoxifene acetate with the hydrophilic compounds.
  • the filler can comprise any substance of this function known in the art for the preparation of the solid oral forms, including the hydrophilic fillers.
  • the pharmaceutically acceptable filler can be selected for example from microcrystalline cellulose, powdered cellulose, siliconized microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate, lactose (e.g. anhydrous or monohydrate), saccharose, raffinose, compressible sugar, glucose, fructose, dextrose and other sugars, sugar alcohols such as mannitol, sorbitol, maltitol, xylitol, lactitol, and mixtures thereof.
  • Preferred excipients are microcrystalline cellulose, lactose and mannitol and any mixtures thereof.
  • binders examples include (but not limited to) polyvinylpyrrolidones of different K-values (i.e. exhibiting different viscosities in solution), microcrystalline cellulose, hydroxypropylmethylcellulose or other cellulose esters, cellulose ethers, starch, pre-gelatinized starch, polymethacrylate and any mixtures thereof.
  • the preferred binders are povidone and pregelatinized starch, the most preferred is pregelatinized starch.
  • the disintegrant shall be selected most preferably from the group of sodium starch glycolate, croscarmelosse sodium, crospovidone and any their mixture. These disintegrants were selected for that they showed contribution to the technical effect of this invention.
  • the surfactant can be selected form the group of sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, sugar esters of fatty acids and glycerides of fatty acids or mixtures thereof.
  • the preferred surfactant is sodium lauryl sulfate.
  • the glidant can be selected from the group of stearic acid and its metallic salts, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols, colloidal silica and any mixtures of thereof.
  • the preferred glidants are metallic stearates and colloidal silica; the most preferred is colloidal silica.
  • Examples of lubricants as excipients include stearic acid or stearic acid salts, such as magnesium stearate, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols, and any mixtures thereof.
  • Preferred is magnesium stearate or sodium stearyl fumarate, mostly magnesium stearate.
  • composition of the tablet core according to the invention comprises:
  • ⁇ optionally up to 5% of glidant
  • ⁇ optionally up to 5% of lubricant
  • the tablet cores can be optionally coated by a commonly used coating.
  • the function of the coating can be as for strengthen the tablet, control its release, improve its taste, colour it, make it easier to handle and package, and protect it from moisture.
  • a moisture protective coating is used.
  • the final tablet can be prepared by method of direct compression, dry granulation, wet granulation, or their combination.
  • the process of preparation of pharmaceutical composition of the present invention by direct compression technique may comprise the following steps:
  • the process of preparation of pharmaceutical composition of the present invention by dry granulation may comprise the following steps:
  • the process of preparation of pharmaceutical composition of the present invention by wet granulation may comprise the following steps:
  • the granulation liquid can be water or its mixtures with pharmaceutically acceptable organic solvents (preferably ethanol) at any ratio, aqueous solution of binders or solution of binders in an organic solvent or its mixture with water at any ratio.
  • the process of preparation of pharmaceutical composition of the present invention by combination of wet granulation and dry granulation may comprise the following steps: a) preparation of first part of granules by dry granulation process comprising:
  • step a) preparation of the pre-mix of apeledoxefine acetate with at least one hydrophilic compound either by
  • Example 1 Composition of 20 mg tablet core
  • Example 2 Methods of preparation of the tablet cores by the dry granulation
  • the tablet cores of the composition shown in the Example 1 were prepared by several different methods of the invention:
  • the micronised apeledoxifene acetate (equivalent to 20 mg apeledoxifene per tablet) was provisionally mixed with lactose monohydrate and sodium lauryl sulphate.
  • the blend was sieved through the screen (0.63 mm) and mixed in a high shear mixer for 10 min (mixer speed 1500 rpm, chopper speed 1800 rpm.
  • the resulting pre-mix was complemented with two thirds of sieved microcrystalline cellulose, two thirds of the sodium starch glycolate and with pregelatinised starch and mixed for 10 minutes in a tubular mixer at 30 rpm.
  • One third of the magnesium stearate was admixed for additional 3 minutes.
  • the blend was granulated using roller-compaction process with a force between 3-7 KN/cm.
  • the compacts were milled through 1.0 mm sieve and resulting granules were mixed with remaining microcrystalline cellulose, sodium starch glycolate and with colloidal anhydrous silica for 10 minutes in turbula mixer at 30 rpm.
  • the remaining magnesium stearate was added and mixed for 3 min in turbula mixer at 30 rpm.
  • the final blend was compressed into 400 mg tablet cores using rotary tablet press.
  • the tablet cores were coated with a moisture protection polymer.
  • the non-micronised apeledoxifene acetate (equivalent to 20 mg apeledoxifene per tablet) was provisionally mixed with part of lactose monohydrate, so that the ratio between the apeledoxifene acetate and lactose was 1 :1.
  • This mix was subjected to the jet-milling at 3 bar pressure.
  • the resulting pre-mix was complemented with the rest of lactose, two thirds of sieved microcrystalline cellulose, two thirds of the sodium starch glycolate and with pregelatinised starch and sodium lauryl sulphate and mixed in a high shear mixer for 5 min (mixer speed 1500 rpm, chopper speed 1800 rpm.
  • magnesium stearate was admixed for additional 3 minutes.
  • the blend was granulated using roller-compaction process and resulting granules were mixed with remaining microcrystalline cellulose, sodium starch glycolate and with colloidal anhydrous silica for 10 minutes in turbula mixer at 30 rpm.
  • the remaining magnesium stearate was added and mixed for 3 min in turbula mixer at 30 rpm.
  • the final blend was compressed into 400 mg tablet cores using rotary tablet press. The tablet cores were coated with a moisture protection polymer.
  • the process of preparation of the tablet cores was similar to the process of example 2a, only the step of pre-mixing of the micronised apeledoxifene acetate with lactose and the sodium lauryl suplhate was not performed.
  • Example 3 Composition of 20 mg tablet core
  • Example 4 Methods of preparation of the tablet cores by the wet granulation
  • the tablet cores of the composition shown in the Example 3 were prepared by several different methods of the invention:
  • the micronised apeledoxifene acetate (equivalent to 20 mg apeledoxifene per tablet) was provisionally mixed with lactose monohydrate and sodium lauryl sulphate.
  • the blend was sieved through the screen (0.63 mm) and mixed in a high shear mixer for 10 min (mixer speed 1700 rpm, chopper speed 2000 rpm).
  • the resulting pre-mix was complemented with two thirds of sieved microcrystalline cellulose, two thirds of the Sodium carboxymethylcellulose and with pregelatinised starch and mixed for 5 minutes in a high shear mixer at 1500 rpm.
  • the blend was wet granulated with aqueous solution of pregelatinised starch using a fluid bed dryer.
  • the resulting granules were mixed with remaining microcrystalline cellulose, Sodium carboxymethylcellulose and with colloidal anhydrous silica for 10 minutes in turbula mixer at 30 rpm.
  • the remaining magnesium stearate was added and mixed for 3 min in turbula mixer at 30 rpm.
  • the final blend was compressed into 400 mg tablet cores using rotary tablet press.
  • the tablet cores were coated with a moisture protection polymer.
  • the non-micronised apeledoxifene acetate (equivalent to 20 mg apeledoxifene per tablet) was provisionally mixed with part of lactose monohydrate and with the sodium lauryl sulphate, so that the ratio between the apeledoxifene acetate and lactose was 1 : 1 .
  • This mix was subjected to the jet-milling at 3 bar pressure.
  • the resulting pre-mix was complemented with the rest of lactose, two thirds of sieved microcrystalline cellulose, two thirds of the Sodium carboxymethylcellulose and with pregelatinised starch and mixed in a high shear mixer for 5 min (mixer speed 1500 rpm, chopper speed 1800 rpm).
  • the blend was wet granulated and further processed as described in the Example 4a.
  • the process of preparation of the tablet cores was similar to the process of example 4a, only the step of pre-mixing of the micronised apeledoxifene acetate with lactose and the sodium lauryl sulphate was not performed.
  • Example 5 Composition of 20 mg tablet core
  • Example 6 Methods of preparation of the tablet cores partially by the wet granulation and partially by the dry granulation
  • the tablet cores of the composition shown in the Example 5 were prepared by several different methods of the invention:
  • the non-micronised apeledoxifene acetate (equivalent to 20 mg apeledoxifene per tablet) was provisionally mixed with part of lactose monohydrate and with the sodium lauryl sulphate, so that the ratio between the apeledoxifene acetate and lactose was 1 : 1.
  • This mix was subjected to the jet-milling at 3 bar pressure.
  • the excipients for the dry granules were blended for 10 minutes in a tubular mixer at 30 rpm.
  • One third of the magnesium stearate was admixed for 3 min at 30 rpm. This lend was compacted with a force between 3-7 KN/cm.
  • the compacts were milled through 1.0 mm sieve.
  • Both parts of granules were blended for 15 min in the turbula mixer at 30 rpm.
  • the resulting blend was lubricated with the rest of the lubricant and compressed into tablet cores.
  • the tablet cores were coated with a moisture protection polymer.
  • the process of preparation of the tablet cores was similar to the process of example 6a, only the step of pre-mixing of the micronised apeledoxifene acetate with lactose and the sodium lauryl sulphate was not performed.
  • Example 8 Dry granulation with different ratios between apeledoxifene acetate and hydrophilic compounds in the pre-mix
  • Tablet cores of composition from the Example 2 were prepared by the method described in the Example 2b (dry granulation, co-grinding) except that different ratios of apeledoxifene acetate and the hydrophilic compounds were tested. The tested ratios are shown in the table below:

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Abstract

Cette invention concerne un procédé de préparation d'un noyau de comprimé comprenant de l'acétate de bazédoxifène, ledit procédé comprenant une étape de préparation d'un prémélange d'acétate de bazédoxifène micronisé avec au moins un composé hydrophile en mélangeant intimement l'acétate de bazédoxifène avec ledit composé hydrophile - en mélangeant intensément l'acétate de bazédoxifène micronisé avec ledit ou lesdits composés hydrophiles ou - en broyant simultanément l'acétate de bazédoxifène avec ledit ou lesdits composés hydrophiles, ledit rapport acétate de bazédoxifène sur composé hydrophile étant compris entre 1:0,5 et 1:6.
PCT/CZ2012/000048 2012-06-07 2012-06-07 Augmentation de la vitesse de dissolution d'une composition pharmaceutique comprenant de l'acétate de bazédoxifène WO2013182170A1 (fr)

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* Cited by examiner, † Cited by third party
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RU2790827C1 (ru) * 2021-09-22 2023-02-28 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Способ получения фармацевтической композиции на основе гексаметилендиамида бис-(n-моносукцинил-l-серил-l-лизина)
CN116036293A (zh) * 2022-12-02 2023-05-02 成都中医药大学 一种青黛干混悬剂及其制备方法

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EP2311805A1 (fr) 2007-07-25 2011-04-20 Zentiva, K.S. Nouvelle forme polymorphique de l'acetate de bazedoxifene
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US5998402A (en) 1996-04-19 1999-12-07 American Home Products Corporation 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
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RU2790827C1 (ru) * 2021-09-22 2023-02-28 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Способ получения фармацевтической композиции на основе гексаметилендиамида бис-(n-моносукцинил-l-серил-l-лизина)
CN116036293A (zh) * 2022-12-02 2023-05-02 成都中医药大学 一种青黛干混悬剂及其制备方法

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