WO2021177930A1 - Pharmaceutical composition with increased solubility of gesperidine and method of its preparation - Google Patents
Pharmaceutical composition with increased solubility of gesperidine and method of its preparation Download PDFInfo
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- WO2021177930A1 WO2021177930A1 PCT/UA2020/000056 UA2020000056W WO2021177930A1 WO 2021177930 A1 WO2021177930 A1 WO 2021177930A1 UA 2020000056 W UA2020000056 W UA 2020000056W WO 2021177930 A1 WO2021177930 A1 WO 2021177930A1
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- hesperidin
- pharmaceutical composition
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
Definitions
- the invention relates to the field of pharmacy, namely to pharmaceutical compositions containing bioflavonoids as active pharmaceutical ingredients, in particular to a pharmaceutical composition containing hesperidin and pharmaceutically acceptable auxiliary substances - solubilizers.
- Hesperidin, 3',5,7-trihydroxy-4'-methoxyflavonone-7-ramoglucoside is a bioflavonoid that has high antioxidant activity, which determines its angioprotective, venoprotective, venotonizing effect.
- Hesperidin is known for its properties of eliminating inflammation, alleviating allergies and asthma, effective in hypo- and avitaminosis, treatment of a number of diseases of the blood vessels, in particular hemorrhagic diathesis, hemorrhages in the retina, radiation sickness. It also eliminates symptoms in menopausal syndrome, activates collagen production and enhances connective tissue properties.
- hesperidin supports and activates the action of many other bioflavonoids and thus enables them to manifest their properties to the fullest [1].
- a known composition with increased bioavailability and the ability to form aqueous microdispersions which are obtained by distributing the active substance (combinations of one or more components of extracts of medicinal plants, in particular flavonoids rutin, quercitin, hesperidine) between chains of the molten biocompatible polymer polyethylene glycol, polyvinyl alcohol, polyalkyl methacrylate, polylactide and its copolymers with glycolic acid, polyethylene oxide, glycyrrhizic acid, cyclodextrin, dextran), followed by cooling and grinding of solid dispersion by ultrasound [4].
- the disadvantage of this method of obtaining a solid dispersion is the prolonged stay of extracts of medicinal plants at elevated temperature during the introduction into the melt of the polymer and grinding by ultrasound, which can lead to their overheating and destruction of biologically active substances.
- the proposed method allows to obtain a hydrophilic drug, which when added to aqueous solutions forms a dispersion of microvesicles and can be used to obtain injection or infusion dosage forms.
- the disadvantage of this method is the use of organic solvents (ligroin, diethyl and petroleum ethers, methyl alcohol, acetone), which is associated with their explosiveness and high toxicity. There is also a risk of residual solvents in the preparation.
- hesperidin- ⁇ - cyclodextrin It is proposed to obtain a solid inclusion complex of hesperidin- ⁇ - cyclodextrin as follows: a solution of hesperidin in methanol was prepared, the solution was kept at 4 ⁇ 2 °C in the dark, and then the methanol was evaporated in a water bath. An aqueous solution of b-cyclodextrin was added to the obtained powder, shaken for 72 h, and then the solvent was removed under reduced pressure [7].
- the basis of the invention is to create a pharmaceutical composition with high solubility of hesperidin and to develop a method for its preparation.
- the pharmaceutical composition containing hesperidin as the active pharmaceutical ingredient is a water-soluble nanosized solid dispersed system "hesperidin - polymer compound", where polyvinylpyrrolidones are used as pharmaceutically acceptable polymeric substances - solubilizers m. w. 2500-58000, and additionally contains the surfactant Tween- 80 in the ratio, wt. %:
- Tween-80 0,1- 1,0
- the method of obtaining the claimed pharmaceutical composition is the interaction of hesperidin with polyvinylpyrrolidone m. w. 2500-58000 with the formation of a water-soluble complex in the presence of Tween-80 in the process of co-dissolving in Pharmacopoeia grade water at a moderate temperature (30-50) ⁇ 5 °C, continuous stirring and subsequent removal of the solvent, the removal of the solvent occurs by evaporation by moderate heating or by vacuum or spray or lyophilic drying, or other well-known methods.
- the technical result of the present invention is to increase the solubility of hesperidin, which is part of the pharmaceutical composition, by 31.4 to 42.7 times depending on the formulation of the composition in comparison with native hesperidin.
- Tween-80 0,1- 1,0
- the most effective composition is the formulation of examples No. 2, 6, 10
- the high solubility pharmaceutical composition of hesperidin is a nanoscale solid dispersion system (TDS), namely a stable water-soluble complex of hesperidin, a pharmaceutically acceptable polymer auxiliary in a 1:1 molar ratio.
- TDS nanoscale solid dispersion system
- the formation of the complex was confirmed by the study of phase solubilization of hesperidin by the Higuchi-Connors method (Figure 1) [10].
- Figure 1 shows the phase solubility profile of TDS hesperidin depending on the qualitative and quantitative composition of the complex.
- the stability constants of the Ks complexes are in the range 201.97- 230.14 M -1 (Table 2).
- compositions of examples 3 to 12 are prepared analogously to the preparation of the composition of example 2.
- the composition of the compositions of example 3 -12 are shown in table. 1.
- the proposed pharmaceutical composition solves the problem of increasing the solubility of hesperidin, and its manufacturing process is high-tech, simple in technological design and does not require sophisticated specialized energy- consuming equipment.
- the proposed method of obtaining a pharmaceutical composition with high solubility hesperidin will allow to develop on its basis dosage forms with high solubility and bioavailability of hesperidin for parenteral, oral, transdermal, sublingual, rectal and intranasal use for the treatment of a wide range of diseases.
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- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
Pharmaceutical composition with high solubility of hesperidin is a water- soluble nanosized solid dispersed system of hesperidin with polyvinylpyrrolidone molar mass 2500-34000 and is obtained by co-dissolving them in the presence of a surfactant Tween 80 in Pharmacopoeia grade water followed by removal of the solvent. Pharmaceutical composition for the treatment of neurodegenerative diseases with high solubility of hesperidin, which is a nanosized solid dispersive system containing the active substance hesperidin and excipients where as solubilizers contains polyvinylpyrrolidones with a molar mass of 2500-58000 and surfactant Tween-80.
Description
PHARMACEUTICAL COMPOSITION WITH INCREASED SOLUBILITY OF GESPERIDINE AND METHOD OF ITS PREPARATION
The invention relates to the field of pharmacy, namely to pharmaceutical compositions containing bioflavonoids as active pharmaceutical ingredients, in particular to a pharmaceutical composition containing hesperidin and pharmaceutically acceptable auxiliary substances - solubilizers.
Hesperidin, 3',5,7-trihydroxy-4'-methoxyflavonone-7-ramoglucoside is a bioflavonoid that has high antioxidant activity, which determines its angioprotective, venoprotective, venotonizing effect. Hesperidin is known for its properties of eliminating inflammation, alleviating allergies and asthma, effective in hypo- and avitaminosis, treatment of a number of diseases of the blood vessels, in particular hemorrhagic diathesis, hemorrhages in the retina, radiation sickness. It also eliminates symptoms in menopausal syndrome, activates collagen production and enhances connective tissue properties. In addition, hesperidin supports and activates the action of many other bioflavonoids and thus enables them to manifest their properties to the fullest [1].
Despite the wide range of pharmacological action, the nomenclature of known drugs containing hesperidin as active ingredient is still limited by oral preparations due to its low solubility in aqueous media and correspondingly low bioavailability [2].
There are a number of methods to overcome the low solubility and bioavailability of poorly soluble active pharmaceutical ingredients: reducing particle size (micronization, spray drying), adding solubilizers, obtaining inclusion complexes and liposomal forms, changing the crystalline state, preparing solid systems.
A known composition with increased bioavailability and the ability to form aqueous microdispersions, which are obtained by distributing the active substance (combinations of one or more components of extracts of medicinal plants, in particular flavonoids rutin, quercitin, hesperidine) between chains of the molten biocompatible polymer polyethylene glycol, polyvinyl alcohol, polyalkyl methacrylate, polylactide and its copolymers with glycolic acid, polyethylene oxide, glycyrrhizic acid, cyclodextrin, dextran), followed by cooling and grinding of solid dispersion by ultrasound [4]. The disadvantage of this method of obtaining a solid dispersion is the prolonged stay of extracts of medicinal plants at elevated temperature during the introduction into the melt of the polymer and grinding by ultrasound, which can lead to their overheating and destruction of biologically active substances.
It’s known about the hydrophilic complex based on flavonolignans and phospholipids, which is obtained by their interaction in an organic medium with subsequent drying of the resulting mixture by lyophilization or spray drying [5]. First, an aqueous dispersion of phospholipids containing a pharmaceutically acceptable saccharide is prepared, and then a mixture of flavonolignans and phospholipids in an acceptable organic solvent is injected into the dispersion. As flavonolignans, phenolic substances are used, in particular silymarin, rutin, hesperidin, quercetin. The proposed method allows to obtain a hydrophilic drug, which when added to aqueous solutions forms a dispersion of microvesicles and can be used to obtain injection or infusion dosage forms. The disadvantage of this method is the use of organic solvents (ligroin, diethyl and petroleum ethers, methyl
alcohol, acetone), which is associated with their explosiveness and high toxicity. There is also a risk of residual solvents in the preparation.
It is known solid nanocomposite with increased bioavailability based on bioflavonoid taxifolin without the use of organic solvents and melting at high temperatures. As a polymer it is proposed to use polyethylene glycol (PEG) (m. w. from 4000 to 8000), polyvinylpyrrolidone (PVP) (m. w. from 7000 to 20,000) or arabinogalactan polysaccharide [6]. However, this method of obtaining a solid nanocomposition is only suitable for the formulation development of solid dosage forms and for use as a carrier of active substances in the production of food.
It is proposed to obtain a solid inclusion complex of hesperidin-β- cyclodextrin as follows: a solution of hesperidin in methanol was prepared, the solution was kept at 4 ± 2 °C in the dark, and then the methanol was evaporated in a water bath. An aqueous solution of b-cyclodextrin was added to the obtained powder, shaken for 72 h, and then the solvent was removed under reduced pressure [7]. The solubility of the solid complex of inclusion of hesperidin^-cyclodextrin was not investigated by the authors, but in the following work showed the increase of solubility and dissolution rate of flavonoids of hesperetin (aglycone hesperidin) and naringenin in buffer medium at pH 8 in the composition of solid inclusion complexes [8].
It is also known that hesperidin forms complexes with 2-hydroxypropyl-β- cyclodextrin, which have limited water solubility [9].
Thus, the authors of the above works only partially solved the problem of increasing the solubility and, accordingly, the bioavailability of bioflavonoids.
The known sources of information to the authors do not know the water- soluble pharmaceutical composition based on hesperidin and how to obtain it.
The basis of the invention is to create a pharmaceutical composition with high solubility of hesperidin and to develop a method for its preparation.
To solve this problem, it is proposed the pharmaceutical composition containing hesperidin as the active pharmaceutical ingredient is a water-soluble
nanosized solid dispersed system "hesperidin - polymer compound", where polyvinylpyrrolidones are used as pharmaceutically acceptable polymeric substances - solubilizers m. w. 2500-58000, and additionally contains the surfactant Tween- 80 in the ratio, wt. %:
Gesperidin 0,1 - 15,0
Polyvinylpyrrolidones 2500-58000 84,0 - 99,8
Tween-80 0,1- 1,0 The method of obtaining the claimed pharmaceutical composition is the interaction of hesperidin with polyvinylpyrrolidone m. w. 2500-58000 with the formation of a water-soluble complex in the presence of Tween-80 in the process of co-dissolving in Pharmacopoeia grade water at a moderate temperature (30-50) ± 5 °C, continuous stirring and subsequent removal of the solvent, the removal of the solvent occurs by evaporation by moderate heating or by vacuum or spray or lyophilic drying, or other well-known methods.
The technical result of the present invention is to increase the solubility of hesperidin, which is part of the pharmaceutical composition, by 31.4 to 42.7 times depending on the formulation of the composition in comparison with native hesperidin.
Laboratory studies of the claimed pharmaceutical composition were carried out by determining the solubility of hesperidin, which is part of nanoscale solid dispersion systems prepared in accordance with examples No. 1 - 12 (table. 1), in comparison with the native hesperidin by UV scanning spectrophotometer Optizen POP (Mecasys, South Korea) at a wavelength of 284 nm.
The substantiation of the choice of qualitative and quantitative formulation of the claimed composition is shown in table 1. The qualitative composition of the claimed composition is selected experimentally. The absence of any ingredient in its composition does not allow to obtain the required technical result.
An essential feature of the invention is the claimed quantitative ratio of the ingredients in the formulation of the claimed pharmaceutical composition.
Any deviations from it do not allow to obtain the necessary effect of increasing the solubility of hesperidin. Limiting (both minimum and maximum) the number of ingredients of the formulation with polyvinylpyrrolidone of different molecular weights are given in examples No. 1, 4, 5, 8, 9, 12, and the average in examples No. 2, 3, 6, 7, 10, 11 (Table 1). Increasing the solubility of hesperidin included in the pharmaceutical composition, and where its quantitative content goes beyond the lower limit of the claimed formulation, does not exceed the preferred variant of the composition (see table. 1, No. 2, 3, 6, 7, 10, 11). As shown by studies in the case of excess content of hesperidin compared to the claimed upper limit of the formulation of the claimed composition, its solubility does not increase. The results of studies of various qualitative and quantitative formulations of the claimed composition are shown in table. 1, show that the ratio is optimal, wt. %:
Gesperidin 0,1 - 15,0
Polyvinylpyrrolidones 2500-58000 84,0 - 99,8
Tween-80 0,1- 1,0 The most effective composition is the formulation of examples No. 2, 6, 10
(table. 1). The solubility of hesperidin in the aqueous medium, depending on the composition of the TDS, increased by 31.4 - 42.7 times compared with native hesperidin (Table 1).
Increasing solubility of hesperidin depending on the composition of TDS compared to native hesperidin
Table 1
The high solubility pharmaceutical composition of hesperidin is a nanoscale solid dispersion system (TDS), namely a stable water-soluble complex of hesperidin, a pharmaceutically acceptable polymer auxiliary in a 1:1 molar ratio. The formation of the complex was confirmed by the study of phase solubilization of hesperidin by the Higuchi-Connors method (Figure 1) [10].
Figure 1 shows the phase solubility profile of TDS hesperidin depending on the qualitative and quantitative composition of the complex.
The stability constants of the Ks complexes are in the range 201.97- 230.14 M-1 (Table 2).
Persistence and dissociation constants of hesperidin complexes with pharmaceutically acceptable excipient PVP K-25 in water at temperatures of 25 ± 0,5 °C, 30 ± 0,5 °C, 37 ± 0,5 °C, 40 ± 0,5 °C
Table 2
The pharmaceutical compositions of examples 3 to 12 are prepared analogously to the preparation of the composition of example 2. The composition of the compositions of example 3 -12 are shown in table. 1.
Example 1.
The formulation of the pharmaceutical composition of example No. 1 are given in table. 1.
Preparation of the composition of example 1. Elesperidin is mixed with PVP K-25 to form a homogeneous mass. Twin-80 is dissolved in purified water. To the solution with stirring was added a mixture of hesperidin and PVP K-25 and continued to stir for 30 min at a temperature of 37 ± 5 °C. Separation of aqueous and solid phases is carried out by filtration through a filter of 0.45 μm. The filtrate (TDS solution) is placed in the oven. The drying process is carried out at 60 ± 0,5 °C to constant weight.
Example 2.
The formulation of the pharmaceutical composition of example No. 2 are given in table. 1.
Preparation of the composition of example 2.
Hesperidin is mixed with PVP K-25 to form a homogeneous mass. Twin-80 is dissolved in purified water. To the solution with stirring was added a mixture of hesperidin and PVP K-25 and continued to stir for 30 min at a temperature of 37 ± 5 °C. Separation of aqueous and solid phases is carried out by centrifugation at 6000 rpm for 30 ± 5 min. The aqueous phase (TDS solution) is decanted and placed in an oven. The drying process is carried out at 60 ± 5 °C to constant weight.
The proposed pharmaceutical composition solves the problem of increasing the solubility of hesperidin, and its manufacturing process is high-tech, simple in technological design and does not require sophisticated specialized energy- consuming equipment.
The proposed method of obtaining a pharmaceutical composition with high solubility hesperidin will allow to develop on its basis dosage forms with high solubility and bioavailability of hesperidin for parenteral, oral, transdermal, sublingual, rectal and intranasal use for the treatment of a wide range of diseases.
Sources
1. Middleton E., Kandaswami C. Effects of flavonoids on immune and inflammatory cell function. Biochem Pharmacol. 1992. V. 43. P. 1167-1179
2. Majumdar S. Solubility, Stability, Physicochemical Characteristics and In Vitro Ocular Tissue Permeability of Hesperidin: a Natural Bioflavonoid. Pharmaceutical Research. 2010. N°26. C.1217-1225)
3.
2012. T. XIX, N° 4. C. 43 - 47.
4.
ΠaT. 2354395 PΦ : MΠK6 A61K 36/00, A61K 31/05, A61K 9, A61K 47/30,
A61K 47/48. N° 2008100633/15; ЗaЯBЛ . 17.01.2008; oпyϬЛ . 10.05.2009,
N° 13. 9 c.
5. CпocoϬ
: ΠaT . 2 310 453 PΦ : MΠK A61K 31/685, A61K 31/352. N° 2006105854/15; ЗaЯBЛ . 28.02.2006; oпyϬЛ . 20.11.2007,
N° 32. 7 c.
6.
ΠaT. WO 2008/123798 : A61K 36/15, A61K 31/79, A61K 31/352, A61K 47/30, A61K 31/715, A61P 43/00. N° PCT/RU2008/000201; ЗaЯBЛ . 02.04.2008; oпyϬЛ . 6.10.2008.
7. Study of flavonoids / β-cyclodextrins inclusion complexes by NMR, FT-IR, DSC, X-rayinvestigation / R. Ficarra, S. Tommasini, D. Raneri [et al.]. Journal of Pharmaceutical and Biomedical Analysis. 2002. Vol. 29. P. 1005- 1014.
8. Improvement insolubility and dissolution rate of flavonoids by complexation with β-cyclodextrin / S. Tommasini, D.Raneri, R.Ficarra [et al.]. Journal of Pharmaceutica land Biomedical Analysis. 2004. Vol. 35. P. 379-387.
9.
2011. N°2. C. 11-12.
10.Higuchi, T., Connors, K.A. Phase-solubility techniques. Adv. Anal. Chem. Instrum. 1965. N° 4. P. 117-122.
Claims
1. Pharmaceutical composition with high solubility of hesperidin, which is a nanoscale solid dispersion system containing the active substance hesperidin and auxiliary substances for solubilization, characterized in that as excipients contains polyvinylpyrrolidone with a molar mass of 2500-58000 and surfactant Tween-80, at the following ratio of components, wt. %:
Gesperidin 0,1 - 15,0
Polyvinylpyrrolidones 2500-58000 84,0 - 99,8
Tween-80 0,1- 1,0
2. A method of obtaining a pharmaceutical composition with high solubility of hesperidin according to claim 1, characterized in that the hesperidin is mixed with polyvinylpyrrolidone molar mass 2500-58000 in the presence of a surfactant Tween-80 in the process of joint dissolution in Pharmacopoeia grade water at a temperature of 37 °C followed by removal of solvent.
3. A method of obtaining a pharmaceutical composition with high solubility of hesperidin according to claim 2, characterized in that the solution of the pharmaceutical composition is filtered before removing the solvent.
4. The method of obtaining a pharmaceutical composition with high solubility hesperidin according to claim 2, characterized in that the solution of the pharmaceutical composition is centrifuged before removing the solvent.
5. A method of obtaining a pharmaceutical composition with high solubility of hesperidin according to claims 2 to 4, characterized in that the removal of the solvent is carried out in vacuum at a temperature not exceeding 40 ± 10°C.
6. A method of obtaining a pharmaceutical composition with high solubility of hesperidin according to claims 2 to 4, characterized in that the removal of the solvent is carried out by spray drying.
7. A method of obtaining a pharmaceutical composition with high solubility of hesperidin according to claims 2 to 4, characterized in that the removal of the solvent is carried out by lyophilization.
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Citations (3)
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| WO2008123798A1 (en) | 2007-04-09 | 2008-10-16 | Otkrytoe Aktsionernoe Obschestvo Zavod Ekologicheskoy Tekhniki I Ekopitaniya 'diod' | Solid nanocomposition for delivering biologically active substances |
| WO2015152433A1 (en) * | 2014-03-31 | 2015-10-08 | Hanmi Pharm. Co., Ltd. | Amorphous solid dispersion comprising paclitaxel, tablet comprising the same, and method for preparing the same |
| KR20160112541A (en) * | 2015-03-19 | 2016-09-28 | 전북대학교산학협력단 | Tissue engineering biodegradable polymer scaffold and a method for manufacturing it |
-
2020
- 2020-05-26 WO PCT/UA2020/000056 patent/WO2021177930A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008123798A1 (en) | 2007-04-09 | 2008-10-16 | Otkrytoe Aktsionernoe Obschestvo Zavod Ekologicheskoy Tekhniki I Ekopitaniya 'diod' | Solid nanocomposition for delivering biologically active substances |
| WO2015152433A1 (en) * | 2014-03-31 | 2015-10-08 | Hanmi Pharm. Co., Ltd. | Amorphous solid dispersion comprising paclitaxel, tablet comprising the same, and method for preparing the same |
| KR20160112541A (en) * | 2015-03-19 | 2016-09-28 | 전북대학교산학협력단 | Tissue engineering biodegradable polymer scaffold and a method for manufacturing it |
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| MAJUMDAR S.: "Solubility, Stability, Physicochemical Characteristics and In Vitro Ocular Tissue Permeability of Hesperidin: a Natural Bioflavonoid", PHARMACEUTICAL RESEARCH., 2010, pages 1217 - 1225 |
| MIDDLETON E.KANDASWAMI C.: "Effects of flavonoids on immune and inflammatory cell function", BIOCHEM PHARMACOL., vol. 43, 1992, pages 1167 - 1179, XP025542458, DOI: 10.1016/0006-2952(92)90489-6 |
| R. FICARRAS. TOMMASINID. RANERI: "Study of flavonoids / (3-cyclodextrins inclusion complexes by NMR, FT-IR, DSC, X-rayinvestigation", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 29, 2002, pages 1005 - 1014 |
| S.TOMMASINID.RANERIR.FICARRA: "Improvement insolubility and dissolution rate of flavonoids by complexation with β-cyclodextrin", JOURNAL OF PHARMACEUTICA LAND BIOMEDICAL ANALYSIS, vol. 35, 2004, pages 379 - 387, XP002433373, DOI: 10.1016/S0731-7085(03)00647-2 |
| ГАВРИЛIН M. B.ЩЕРБАКОВА M. B.MAP O A O. M.: "Пiдвищення ро3чинностi гестеридина 3 використанням 2-гiдроксипропiл-β-цилодекстрина", ΦАРМАЦIЯ, 2011, pages 11 - 12 |
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