WO2011063774A2 - Pectin complexes of steroids and pharmaceutical compositions based thereon - Google Patents

Pectin complexes of steroids and pharmaceutical compositions based thereon Download PDF

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WO2011063774A2
WO2011063774A2 PCT/CZ2010/000120 CZ2010000120W WO2011063774A2 WO 2011063774 A2 WO2011063774 A2 WO 2011063774A2 CZ 2010000120 W CZ2010000120 W CZ 2010000120W WO 2011063774 A2 WO2011063774 A2 WO 2011063774A2
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Prior art keywords
pectin
complex
weight
acid
completely
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PCT/CZ2010/000120
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English (en)
French (fr)
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WO2011063774A3 (en
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Vladimir Kral
Zbynek Oktabec
Josef Jampilek
Tomas Pekarek
Bohumil Proksa
Jiri Dohnal
Anna Malovikova
Anna Ebringerova
Anna Rezacova
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Zentiva, K.S.
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Publication of WO2011063774A2 publication Critical patent/WO2011063774A2/en
Publication of WO2011063774A3 publication Critical patent/WO2011063774A3/en

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • 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
    • A61K31/575—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
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • the present application relates to water-soluble complexes of steroids with pectins.
  • the active substance is in the form of an adduct (complex) with a pectin or a modified pectin.
  • the resulting adduct is characterized by higher solubility in water as compared with the original pharmaceutically active substance.
  • the adduct (complex) composed of the active substance and a pectin is then used for preparing a pharmaceutical composition for obtaining medical dosage forms with targeted release in the intestine.
  • the active pharmaceutical ingredient is a substance with ability to interact with a human or animal organism.
  • the result of this interaction is therapy or prophylaxis of a disease in humans or animals; medical diagnosing or restoration, adaptation or influencing of their physiological functions.
  • Solubility in different solvents is a characteristic property of the given substance.
  • the active substance For achieving pharmacological activity of an API, the active substance should be well soluble in physiological fluids so that it would be available at the place of absorption. Solubility of the substance in water correlates significantly with its solubility in physiological fluids and is the first limiting factor of good absorption and thus bio-distribution. Concerning pharmaceutical formulation, trouble-free substances are those with solubility in water higher than 1%. In case this condition is not met, a solution is sought how to increase solubility.
  • solubility of a medicine can be influenced by two methods - chemical (formation of salts provided the molecule can be ionized; synthetic modification of the molecule for increasing hydrophilicity; preparation of so-called prodrugs) or physical (by addition of auxiliary substances, or solubilizers).
  • solubility is an important factor but also speed of dissolving, i.e. rate of transfer of the dissolved substance into the solution.
  • This is a physical-chemical property that can be influenced by the shape of crystals (crystal modifications, polymorphs), particle size, surface properties of the substance, and the like.
  • solubility is an important factor but also speed of dissolving, i.e. rate of transfer of the dissolved substance into the solution.
  • This is a physical-chemical property that can be influenced by the shape of crystals (crystal modifications, polymorphs), particle size, surface properties of the substance, and the like.
  • solubility of PAMBA p-aminobenzoic acid
  • Association of API with cyclodextnn depends on size of cyclodextrin cavity, on effective dimensions of the complexed substance, and, last but not least, on non-bonding interactions of API and cyclodextrin.
  • certain disadvantage of this method of increasing solubility is low selectivity of complexing, as well as the fact that the cyclodextrins themselves are not completely biologically inert.
  • soluble salts of organic polybasic acids and hydroxyacids have also a character of molecular complexes.
  • Solubility can also be increased by adding surface-active substances - surfactants/detergents. These substances form micelles in aqueous environment. Hydrophilic parts of the surfactant molecule are oriented to outer aqueous environment; on the contrary, lipophilic parts of the molecule are oriented to the micelle centre. Thischingvesicle" can enclose a low-soluble API.
  • Another method is based on using co-solvents - mostly alcohols - usually ethanol, glycerol, propyleneglycol or polyethyleneglycols.
  • Pectin is a natural substance, a polymer composed of saccharide units the basic structure of which consists of a chain of poly a-(l ⁇ 4)-D-galacturonic acid alternating with a-(l ⁇ 2)-L- rhamnosyl-a-(l- ⁇ 4)-D-galacturonosyl sections.
  • the basic chain can be branched; the side chain typically contains neutral saccharides, such as L-arabinose, D-galactose, D-xylose, etc.
  • the carboxyl groups of D-galacturonic acid can be methylated; properties of the pectin then depend on the degree of esterification.
  • pectins In the presence of bivalent cations, mainly calcium, low-methylated pectins form a gel. High-methylated pectins (with more than 45% of esterified carboxyl groups) can also form a gel. However, this property results from formation of hydrogen bonds and hydrophobic interactions at pH about 3 or in the presence of saccharides.
  • Another method of modifying the basic skeleton of pectin consists in replacement of the methyl groups of the D-galacturonic acid ester by other alkyl or arylalkyl groups; in addition, a possibility exists of replacing the ester group by an amide, mono- or dialkylamide group. Pectins
  • Pectins which have so far been used predominantly as food additives, are a group of heteropolysaccharides of variable composition. They contain at least 65% by weight of galacturonic acid as the basic structural unit. This can be present as free acid, the methylester, amidated pectin or acetamide.
  • Formula 1 depicts the structure of the pectin monomer unit composed of galacturonic acid, ester, and amide group.
  • Formula 2 depicts the structure of the pectin chain composed of galacturonic acid.
  • Pectins intended for use are formed of a linear chain containing at least 65% by weight of D- galacturonic acid units. This ' polymer is often called polygalacturonic acid. Units of galacturonic acid in the chain can be either free or naturally esterified with methanol to different degrees (67 - 73% by weight, on average).
  • pectins are formed from more complex protopectins, which are present in plant tissues and contain also various neutral saccharides, including rhamnose, galactose, arabinose, and smaller amounts of other saccharides. These saccharide units are present in an irregular structure. Using of purified enzyme has proved that a pectin extract prepared under very mild conditions contains both linear blocks composed of homopolygalacturonic acid.
  • Linear sequences of units of a-D-galacturonic acid are terminated with an a-L- rhamnopyranose unit bound by an a-(l ⁇ 2) glycosidic bond.
  • the content of rhamnose in pectins is usually 1 to 4% by weight. These sections of the pectin molecule are called rhamnogalacturonans.
  • pectins also contain various neutral saccharides in side chains. L-Arabinose and D- galactose are present in greatest amounts. D-Xylose, D-glucose, D-mannose, L-fucose, and D- gluconic acid are present less frequently.
  • pectins have been used in pharmaceutics as active substances in treating diabetes (US 2007/0167395); for control of blood glucose level (CN1883501); therapy of ulcer disease in combination with colloidal bismuth (CN1698895; CN1634132); as anti-tumour substances after pectin depolymerization (WO2006/002106); as transdermal delivery form of a pectin gel with an opioid (WO2005/102294); microcapsules composed of combination of a pectin and an alginate for formulation of folic acid (Madziva, H. et al. J.
  • pectin was used in combination with inulin (RU2169002), or lactoferrin (WO2002047612); in combination with oat bran, glucosamine for elimination of non-digested fat (US 6 200 574, US 5 891 441); as a component of hydrophilic matrix in combination with a plant protein, dextrin, and sucrose, pectin was used for formulation of carotenoids (WO2007/017539); covalently bound anti-tumour substances with a pectin were designed as a prodrug for targeted transport of API (CN101045163); pectin was used for a gastroresistant formulation of rifaximin in therapy of inflammatory diseases of stomach (WO2006/094737); pectin was used for encapsulation of lipophilic vitamins (US2005/0238675); as an active substance for removing cholesterol from the body (MD2518); as a substance stabilizing favorpectin/heparin binding growth factors" (US 6
  • Another field of pectin application is preparation of dosage forms, typically gel-based in the presence of calcium for controlled release of the drug in the lower part of GIT (Chourasia M.K., Jain S.K. J. Pharm. Sci. 2003, 6, 33; Sinha V.R., Kumria R. Int. J. Pharm. 2001, 224, 19), such as, for example, a formulation of venlafaxine in combination with polyvinylpyrrolidone (US 6 703 044); a formulation of metal-specific enzymes (WO2008/059062); theophylline (Wu B. et al. Eur. J. Pharm. Biopharm.
  • microsponges with HPMC (Orlu M. et al. Int. J. Pharm. 2006, 318, 103); 5-aminosalicylic acid in combination with HPMC (Turkoglu M. et al. Eur. J. Pharm. Biopharm. 2002, 53, 65); ropivacaine (Ahrabi S.F. et al. Eur. J. Pharm. Sci. 2000, 10, 43); budesonide in combination with guar gum (EP 0 974 344); corticosteroids (US 5 849 327; WO97/25980); in combination with xyloglucan for oral administration (Itoh K. et al. Int. J. Pharm.
  • pectin was used in dosage forms using adhesion onto buccal mucosa (US2004/0241223; Nafee N.A. et al. Drug Dev. Ind. Pharm. 2004, 30, 985); adhesion onto intestinal mucosa (Shen Z. et al. Pharm. Res. 2002, 19, 391); in combination of pectin and HPMC (Miyazaki S. et al. Int. J. Pharm.
  • transdermal applications W097/43989; EP 0 719 135; IN 192518; EP 0 975 367
  • in ocular applications in combination of pectin with a polyacrylate or polyvinylalcohol in combination of pectin with a polyacrylate or polyvinylalcohol (Chetoni P. et al. Boll. Chim. Farm. 1996, 135, 147).
  • pectin was used in formulation of calcitonin in a pectin-liposomal complex (Thirawong N. et al. J. Contr. Rel. 2008, 125, 236), and of various therapeutic peptides (WO2007/ 129926) and insulin (Cheng K., Lim L.Y. Proc. Int. Symp. Contr. Rel. Bioact. Mat. 2000, 27, 992).
  • Complexes of DNA and cationic lipids prepared by microencapsulation were also prepared in the presence of pectins (Harvey R.D. et al. NanoBiotechnology 2005, 1, 71).
  • natural or chemically modified polysaccharides are mostly used, such as inulin, amylose, pectins, dextran, chitosans, chondroitin, etc.
  • the drug can be then released from them in the intestine by simple change of pH of the environment or by decomposition activated by intestinal microflora (Kumar P. et al. Curr. Drug Delivery 2008, 5, 186; Patel M.M. et al. Pharm. Dev.technik. 2009, 14, 62, Schacht E. et al. J. Control Release 1996, 39, 327; Rama P.Y.V. et al. J. Control Release 1998, 51, 281 ; Tozaki H. et al. J. Pharm.
  • the invention provides water-soluble complexes of steroids with pectins, or with pectin derivatives obtained by re-esterification or by amidation. Surprisingly, formation of such complexes, or adducts, results in increased solubility of steroidal pharmaceutical active substances (API) in water. This effect is of great importance for utilization of these substances in pharmaceutics.
  • API steroidal pharmaceutical active substances
  • the adducts are prepared by stirring an aqueous solution of the pectin with a solution of the API in a water-miscible solvent (for instance, methanol or ethanol). After the complex formation is complete, either the organic solvent is evaporated and the aqueous suspension is used for preparation of the dosage form, or the solvents are evaporated and the solid evaporation residue is used for preparation of the dosage form.
  • a water-miscible solvent for instance, methanol or ethanol
  • the invention provides a pharmaceutical composition, characterized in that the steroidal active substance (API) is in the form of an adduct with a pectin. Surprisingly, formation of such adducts results in increased solubility of lipophilic, low-soluble active substances (API) in water.
  • API steroidal active substance
  • model API's The structures of model API's are shown below.
  • Solubility of a substance is its characteristic property that can be influenced chemically, in particular by preparing prodrugs, or physically by using various auxiliary complexing substances. Owing to the wide pharmaceutical acceptability of pectins documented above as well es their variability, allowing the fine tuning of their complexing properties through the proper substitution, the exploitation of complexes according to this invention for steroid solubilization represents an exceptionally advantageous option among plenty of other excipients potentially useful for the same purpose.
  • the complexes according to invention can be used for preparing pharmaceutical compositions in which the active substance is in the form of an adduct with a pectin, together with one or more pharmaceutically acceptable excipients.
  • a medicinal product prepared using these complexes can have significantly better properties than a non-complexed drug; it has considerably higher solubility, bioavailability and stability.
  • Steroidal API included in complexes according to the invention can be a a natural steroid hormone or any synthetic deri vative in which the steroid carbon skeleton can be identified.
  • the adducts are prepared by stirring an aqueous solution of the pectin with a solution of the API in a water-miscible solvent (for instance, methanol ethanol or acetone). After the complex formation is complete, either the organic solvent is evaporated and the aqueous solution is used for preparing the dosage form, or the solvents are evaporated and the solid evaporation residue is used for preparing the dosage form.
  • a water-miscible solvent for instance, methanol ethanol or acetone
  • water-immiscible solvents such as, for instance, toluene, dichloromethane, chloroform, esters of acetic acid with C 2 -C 5 alcohols, or alcohols having carbon atoms number of C 4 -C 6 can be used as a solvent for the complex-forming API.
  • the formation of the complex can be then easily followed by a spectroscopical estimation of the growing API concentration in the aqueous phase.
  • the complex-containing aqueous phase can be either directly used for the preparation of a pharmaceutical dosage form, or dried and the solid complex subsequently used for the same purpose.
  • the pectin used for the complex preparation can be polygalacturonic acid or a mixture composed of derivatives of this acid.
  • Polygalacturonic acid derivative can be selected from the group consisting of: free acid, acid ester or amide, preferably in the form of the methylester or acetamide.
  • the pectin can contain 65% and more weight units of galacturonic acid; preferably the content of galacturonic acid is more than 80% by weight. Modification of the pectin, i.e. modification of the carboxylate to the respective esters is usually less than 15%.
  • the esters are formed with Ci-Cio alcohols and further with benzylalcohol or cholesterol.
  • the amide derivatives of pectins used include the respective amides prepared by aminolysis of the esters, wherein the amide is derived from primary and secondary amines with 1 to 10 carbon atoms.
  • the molecular weight of the pectin derivatives is usually higher than 1 ⁇ 10 5 Dalton, preferably it ranges between 150 and 120 kD.
  • the pectin can be a polymer composed of saccharide units the basic structure of which is a chain of poly a-(l ⁇ 4)-D-galacturonic acid alternating with a-(l ⁇ 2)-L-rhamnosyl-a-(l ⁇ 4)- D-galacturonosyl sections; the basic chain can be branched and the side chain contains the neutral saccharides pentoses and hexoses and the carboxyl group can be esterified by Ci-C 12 aliphatic alcohols or monoalkyl- or dialkyl-amidated with Ci-C 6 alkyls.
  • the solubility of the pectin derivatives which can be used for the preparation of the complexes according to the invention ranges between 0.1 and 20% by weight in water in the pH range of 5 to 10.
  • compositions prepared according to the invention can be used, for example, for: - Controlled and targeted transport of hydrophobic or hydrophilic drugs;
  • Topical dosage forms containing 1 to 30% by weight of API
  • the final dosage form may further contain a matrix, which is preferably composed of the sodium salt of dextran or the sodium salt of carboxymethylcellulose.
  • FT-Raman spectra were accumulated by FT-Raman spectrometer RFS 100/S (Bruker, Germany); accumulation of 256 scans resolution 4 cm “1 ; laser power 250 mW.
  • Solubility of testosterone-propionate in an aqueous solution of pectin I at pH 3; 5.2; and 6 was estimated to be 0.62 mg of testosterone propionate in 1 mg of pectin in an aqueous solution of concentration 5 mg pectin/ml. Solubility is virtually unchanged with changing pH.
  • Fig. 1 NIR spectra of a pectin I/cholesterol complex (on the top centre) compared with the starting materials cholesterol (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 2 NIR spectra of a pectin I/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 3 NIR spectra of a pectin I/cholic acid complex (on the top centre) compared with the starting materials cholic acid (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 4 NIR spectra of a pectin I/dehydrocholic acid complex (on the top centre) compared with the starting materials dehydrocholic acid (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 5 NIR spectra of a pectin I/pregnenolone acetate complex (on the top centre) compared with the starting materials pregnenolone acetate (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 6 NIR spectra of a pectin I/androstan-3,17-dione complex (on the top centre) compared with the starting materials androstan-3,17-dione (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 7 NIR spectra of a pectin I/testosterone propionate complex (on the top centre) compared with the starting materials testosterone propionate (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 8 NIR spectra of a pectin II/cholesterol complex (on the top centre) compared with the starting materials cholesterol (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 9 NIR spectra of a pectin II/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 10 NIR spectra of a pectin Il/cholic acid complex (on the top centre) compared with the starting materials cholic acid (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 11 NIR spectra of a pectin Il/dehydrocholic acid complex (on the top centre) compared with the starting materials dehydrocholic acid (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 12 NIR spectra of a pectin II/pregnenolone acetate complex (on the top centre) compared with the starting materials pregnenolone acetate (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 13 NIR spectra of a pectin II/androstan-3,17-dione complex (on the top centre) compared with the starting materials androstan-3,17-dione (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 14 NIR spectra of a pectin II/testosterone propionate complex (on the top centre) compared with the starting materials testosterone propionate (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 15 NIR spectra of a pectin Ill/cholesterol complex (on the top centre) compared with the starting materials cholesterol (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 16 NIR spectra of a pectin III/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 17 NIR spectra of a pectin Ill/cholic acid complex (on the top centre) compared with the starting materials cholic acid (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 18 NIR spectra of a pectin Ill/dehydrocholic acid complex (on the top centre) compared with the starting materials dehydrocholic acid (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 19 NIR spectra of a pectin III/pregnenolone acetate complex (on the top centre) compared with the starting materials pregnenolone acetate (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 21 NIR spectra of a pectin Ill/testosterone propionate complex (on the top centre) compared with the starting materials testosterone propionate (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 22 NIR spectra of a sec.dibutylamide of pectan IV/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and sec.dibutylamide of pectan IV (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 23 Raman spectra of a pectin I/cholesterol complex (on the top centre) compared with the starting materials cholesterol (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 24 Raman spectra of a pectin I/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 25 Raman spectra of a pectin I/cholic acid complex (on the top centre) compared with the starting materials cholic acid (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 26 Raman spectra of a pectin I/dehydrocholic acid complex (on the top centre) compared with the starting materials dehydrocholic acid (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 27 Raman spectra of a pectin I/pregnenolone acetate complex (on the top centre) compared with the starting materials pregnenolone acetate (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 28 Raman spectra of a pectin I/androstan-3,17-dione complex (on the top centre) compared with the starting materials androstan-3,17-dione (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 29 Raman spectra of a pectin I/testosterone propionate complex (on the top centre) compared with the starting materials testosterone propionate (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 30 Raman spectra of a pectin II/cholesterol complex (on the top centre) compared with the starting materials cholesterol (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 31 Raman spectra of a pectin II/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 32 Raman spectra of a pectin Il/cholic acid complex (on the top centre) compared with the starting materials cholic acid (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 33 Raman spectra of a pectin Il/dehydrocholic acid complex (on the top centre) compared with the starting materials dehydrocholic acid (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 34 Raman spectra of a pectin II/pregnenolone acetate complex (on the top centre) compared with the starting materials pregnenolone acetate (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 35 Raman spectra of a pectin II/androstan-3,17-dione complex (on the top centre) compared with the starting materials androstan-3,17-dione (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 36 Raman spectra of a pectin II/testosterone propionate complex (on the top centre) compared with the starting materials testosterone propionate (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 37 Raman spectra of a pectin Ill/cholesterol complex (on the top centre) compared with the starting materials cholesterol (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 38 Raman spectra of a pectin Ill/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 39 Raman spectra of a pectin Ill/cholic acid complex (on the top centre) compared with the starting materials cholic acid (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 40 Raman spectra of a pectin Ill/dehydrocholic acid complex (on the top centre) compared with the starting materials dehydrocholic acid (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 41 Raman spectra of a pectin Ill/pregnenolone acetate complex (on the top centre) compared with the starting materials pregnenolone acetate (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 42 Raman spectra of a pectin III/androstan-3,17-dione complex (on the top centre) compared with the starting materials androstan-3,17-dione (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).
  • Fig. 43 Raman spectra of a pectin Ill/testosterone propionate complex (on the top centre) compared with the starting materials testosterone propionate (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

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