WO2014019556A1 - Alaptide : procédé de solubilisation, et de modification de la perméation membranaire, et compositions pharmaceutiques pour applications humaines et/ou vétérinaires - Google Patents

Alaptide : procédé de solubilisation, et de modification de la perméation membranaire, et compositions pharmaceutiques pour applications humaines et/ou vétérinaires Download PDF

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WO2014019556A1
WO2014019556A1 PCT/CZ2012/000074 CZ2012000074W WO2014019556A1 WO 2014019556 A1 WO2014019556 A1 WO 2014019556A1 CZ 2012000074 W CZ2012000074 W CZ 2012000074W WO 2014019556 A1 WO2014019556 A1 WO 2014019556A1
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alaptide
pharmaceutical compositions
fact
compositions according
excipient
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Josef JAMPÍLEK
Radka OPATŘILOVÁ
Anna ŘEZÁČOVÁ
Zbyněk OKTÁBEC
Jiři DOHNAL
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University Of Veterinary And Pharmaceutical Sciences Brno Faculty Of Pharmacy
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Priority to PCT/CZ2012/000074 priority Critical patent/WO2014019556A1/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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/499—Spiro-condensed pyrazines or piperazines
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • 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
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • Alaptide Methods of Effecting its Solubility, Membrane Permeation and Pharmaceutical Compositions for Human and/or Veterinary Applications.
  • the invention deals with the way of influencing the solubility of (S)-8-methyl-6,9- diazaspiro[4.5]decan-7,10-dione, known by the international non-proprietary name of "alaptide", by the addition of low-molecular or high-molecular compounds or generation of nanoparticles.
  • alaptide influence the penetration of alaptide through biological membranes, including skin.
  • Alaptide modified in this way can be also used for preparation of pharmaceutical compositions (formulations), which can, in their turn, influence the absorption of alaptide.
  • Alaptide (5 8-methyl-6,9-diazaspiro[4.5]decan-7,10-dione (see Fig. 1), is a compound discovered in the 1980s at Prague by Kasafirek et al. The substance preparation, production procedures and therapeutic application were protected by a number of patents in Czechoslovakia/the Czech Republic and abroad. Alaptide can be classified as an analogue of melanocyte-stimulating hormone release-inhibiting factor (MIF), also known as Pro-Leu-Gly- NH 2 , i.e. L-prolyl-L-leucylglycinamide. The application of MIF alone as a therapeutic agent is impossible due to its fast enzymatic hydrolysis.
  • MIF melanocyte-stimulating hormone release-inhibiting factor
  • Alaptide was selected from the series of prepared spiro derivatives as the most advantageous MIF analogue from the point of view of enzymatic stability and its pharmacodynamic profile. Alaptide showed significant curative effect in different therapeutic areas on experimental animal models. Alaptide was tested on diploid cell line of human embryonic lung LEP-19 with concentration 5, 10 and 100 ⁇ g/mL of media, where it expressed stimulating effect on growth and breeding of cells without transformation changes in their morphology. In vitro tests also showed that alaptide increased cell proliferation, and both above mentioned effects can significantly contribute to curative alaptide effect. An influence of alaptide on epidermal regeneration was investigated in a number of tests.
  • Alaptide probably negatively affects the inhibition of the release of melanocyte-stimulating hormone and thus it increases the concentration of melanocytes in epidermis.
  • Melanocytes significantly influence the creation and function of keratinocytes by means of melanosomas. (McGrath J.A., Eady R.A., Pope F.M. Rook's textbook of dermatology, 7th ed. Blackwell Publishing, 2004, pp.3-7; James W., Berger T. Elston D. Andrews' diseases of the skin: Clinical dermatology, 10th ed. Saunders, 2005, pp. 5-6).
  • Keratinocytes migrate from stratum basale through stratum spinosum and stratum granulosum to stratum corneum, where they support epidermis regeneration. ⁇ Watt F.M. The epidermal keratinocyte. BioEssays 1988, 8,
  • alaptide is a significant chemical transdermal penetration modifier. Based on the excellent enhancement activity, both alaptide enantiomers were tested in metabolic and induction studies on primary human hepatocyte cultures (Biopredic International, Rennes, France). It was found that alaptide enantiomers do not induce biotransformation enzymes CYP1A1, CYP1A2 and CYP1B1 in hepatocytes, in concentration 20 ⁇ . These biotransformation enzymes are critical in bioactivation of procarcinogens (such as polychlorinated aromatic hydrocarbons or planar hydrocarbons) and are upregulated also by ultraviolet-B radiation (UVB) in the skin.
  • procarcinogens such as polychlorinated aromatic hydrocarbons or planar hydrocarbons
  • CYPlAl is involved in the metabolic activation of aromatic hydrocarbons from pollution or industry contamination (polycyclic aromatic hydrocarbons such as benzopyren, BP) by transforming it to BP-7,8-dihydrodiol-9,10- epoxide, which is the ultimate carcinogen.
  • UVB-mediated induction of cytochromes CYPlAl and CYP1B1 in human skin will probably result in enhanced bioactivation of polycyclic aromatic hydrocarbons and other environmental pollutants to which humans are exposed, which in turn could make the human skin more susceptible to UVB-induced skin cancers or allergic and irritant contact dermatitis.
  • the solubility of the API in physiological liquids is required, so that the API could be available at the place of absorption.
  • Solubility in various solvents is a characteristic property of the particular compound.
  • the solubility of a compound in water correlates to a great extent with the solubility in physiological liquids and is the first limiting factor for good absorption and biodistribution.
  • compounds with the solubility higher than 1 % can be considered as satisfactory.
  • Solubility is not the only important factor; also solubility rate is essential. This is a physico-chemical property that can be ' influenced by crystal shape (morphology, polymorphism), particle size, properties of compound surface, etc.
  • the solubility of an API can be principally influenced in two ways - i) chemically (salt formation when the molecule is ionizable; other molecule modification to increase hydrophilicity; prodrug preparation), or ii) by optimization of physico-chemical properties (addition of excipients or nanoparticle preparation).
  • solubility There are several ways to improve API solubility based on physical methods - formation of molecular complexes with solubilizers (e.g., benzoate sodium with caffeine), but the most widely used solution is inclusion complexes with natural or synthetically modified cyclodextrins.
  • Solubility can be also increased by addition of surfactants/tensides that create micelles in the aqueous medium. Hydrophilic parts of a surfactant molecule are oriented to outside aqueous medium, whereas lipophilic parts of the molecule are oriented inside the micelle. It is possible to enclose a poor soluble API into this cavity.
  • One more frequently used method of solubility increase is complexation of API to polysaccharide matrixes (native or chemically modified), for example, of pectins, glucans, chitosans, celluloses, alginates, etc. (Rabiskova M. et al. Technology of Pharmaceutics, 3rd ed., Galen Prague, 2006).
  • Nanoparticles can be prepared either by the process of dispergation, which supposes breakage of larger micrometer particles to nanoparticles, or by precipitation process.
  • the drug is dispersed in the aqueous solution of a surface modifier.
  • the formed suspension is milled by means of a ball mill in the presence of milling medium.
  • This process is based on the principle of cavitation, consisting in gradual formation, growth and implosive collapse of vapour bubbles in liquid.
  • the main advantage of the high-pressure homogenization is that it can be used both at laboratory preparation and for large-scope production, because various sizes of high-pressure homogenizers are produced.
  • minimal contamination of nanoparticles is induced during this process, which is one of the aims of their production.
  • An API in an organic solvent is dispersed in the aqueous phase containing a surfactant. Then the organic solvent is evaporated under low pressure, and the formed suspension of nanoparticles is stabilized by addition the surfactant.
  • Aqueous, organic or aqueous-organic solution, emulsion or suspension of an API is atomized in cryogenic liquid such as nitrogen.
  • cryogenic liquid such as nitrogen. The result of this procedure is frozen nanoparticles that are subsequently lyophilized.
  • API solution is warmed in an organic solvent with a low boiling point at the pressure that would allow achieving higher temperature than the boiling point of this solvent under normal conditions.
  • Atomization is performed by a heated aqueous solution containing a convenient stabilizing surfactant.
  • Liquid carbon dioxide is mixed with an organic solvent containing an API.
  • the solvent with the API gradually penetrates to liquid carbon dioxide, by which the concentration of the dissolved API is increased. Precipitation or crystallization from the solution takes place after the solution becomes oversaturated.
  • alaptide in formulations (ointments, creams and gels) can be expected in relationship to the above mentioned properties.
  • veterinary ointment Alaptid ® made by Bioveta a.s., Czech Republic is marketed (formulation composition: Polysorbatum 60, Alcohol cetylstearylicus, Paraffinum liquidum, Propylenglycolum, Methylparabenum, Propylparabenum, Aqua pro iniectione).
  • alaptide is used as a component of cosmetic series Cytovital ® of Energy Group a.s., Czech Republic (formulation composition: water, herbal extract, cetylstearyl alcohol, shea butter, fructose, hydroxide sodium, white vaseline, cyclopentadimethylsiloxane, benzoate esters, acetic acid, hemp oil, linseed oil, soya bean oil, tocopherol acetate, ethoxylated castor oil, poppy oil, benzyl alcohol, carbopol, azelaic acid, perfume, palmitoyl ascorbate, retinyl acetate, alaptide, dehydroacetic acid, BHT, succinic acid, vermesin, helixin, energins, zinc acetate).
  • formulation composition water, herbal extract, cetylstearyl alcohol, shea butter, fructose, hydroxide sodium, white vaseline, cyclopentadimethylsiloxane, be
  • compositions of formulations that cart contain the above-mentioned modifiers of physical properties
  • suspension formulations and formulations where alaptide is dissolved in the ointment, cream or gel bases can be used and applied. It can be assumed that pharmaceutical formulations with alaptide will have beneficial effect on regeneration of injured skin.
  • the subject matter of the invention is a new pharmaceutical composition with modified absorption through the skin for human and/or veterinary application characterized by the fact that alaptide with structural formula / is used in the form of a complex and/or a mixture with excipients with amphiphilic and/or complexing properties.
  • amphiphilic compounds the following compounds are used: Tween 20, Tween 80, Macrogol 300, Macrogol 4000, Macrogol 6000, sodium lauryl sulfate, Cremophor EL, Poloxamer, propylene glycol, Arlatone 970, ⁇ -glucan or its polysynthetic modifications, ⁇ -, ⁇ - or ⁇ -cyclodextrins or hydroxypropyl- ⁇ -cyclodextrin or their polysynthetic modifications, methylcellulose and its derivatives or carboxymethyl cellulose and its derivatives or its sodium salts, sodium carboxymethyl dextran, pectins or their salts or their polysynthetic modifications/derivatives.
  • the invention deals with new pharmaceutical compositions with modified absorption through the skin for human and/or veterinary applications characterized by the fact that alaptide is used in the form of a complex and/or a mixture with excipients with amphiphilic and/or complexing properties.
  • amphiphilic compounds the following compounds are used: Tween 20, Tween 80, Macrogol 300, Macrogol 4000, Macrogol 6000, sodium lauryl sulfate, Cremophor EL, Poloxamer, propylene glycol, Arlatone 970, ⁇ -glucan or its polysynthetic modifications, ⁇ -, ⁇ - or ⁇ -cyclodextrins or hydroxypropyl- -cyclodextrin or their polysynthetic modifications, methylcellulose and its derivatives or carboxymethyl cellulose and its derivatives or its sodium salts, sodium carboxymethyl dextran, pectins or their salts or their polysynthetic modifications/derivatives.
  • the formulation according to this invention can be used in the combination with non-steroidal anti-inflammatory drugs (otherwise non-steroidal antiphlogistics or NSADDs) and/or antipyretics/non-opiate analgesics and/or opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics (antibacterials/antimycobacterials, antimycotics, antivirotics) and/or antiparasitics and/or antihaemorrhagics in concentration from 0.001 to 30% (w/w).
  • NSADDs non-steroidal antiphlogistics
  • complexes/adducts are prepared by mixing aqueous solutions of solubilizing or complexing agents with alaptide. After completion of mixing a liquid complex/adduct is used for preparation of drug formulations, or the solvent is evaporated, and the obtained evaporation solid residue (a product of complexation) is consequently used for the preparation of pharmaceutical compositions (formulations).
  • Nanoparticles of alaptide are prepared by mixing alaptide with emulgators and other stabilizers.
  • the subject matter of the invention is original pharmaceutical compositions for human and/or veterinary applications characterized by the fact that the utilized excipients or combinations of excipients modify the solubility of alaptide in the ointment, cream or gel base and simultaneously modify the permeability of alaptide through the skin or act as a transport system.
  • compositions are convenient for treatment of skin and mucosal lesions, e.g., burns, raws, decubituses and venous ulcerations.
  • the therapy of such skin lesions is very difficult, long-standing and not always quite successful, therefore it is suitable to have available as broad variety of effective therapeutics as possible.
  • Pharmaceutical compositions containing alaptide can be used for formulation of alaptide alone and for combination of alaptide with other drugs.
  • the subject matter of the invention is the way of increasing the solubility of alaptide and modification of the penetration of alaptide as well as original pharmaceutical compositions for human and/or veterinary applications characterized by the fact that utilized excipients or combinations of excipients modify the solubility of alaptide in the ointment, cream or gel base and simultaneously modify the permeability of alaptide through the skin or act as a transport system.
  • Alaptide alone is poorly soluble; its solubility in water is 0.1104 g/100 mL, in ethanol 0.1011 g/100 mL, in the mixture water:ethanol 1:1 0.3601 g/100 mL and in hexane 0.0024 g/100 mL; its log Pw/oct is 1.39.
  • Alaptide can be effectively dissolved in aqueous solutions containing surfactants such as Tween 20, Tween 80, Macrogol 4000, Macrogol 6000, propylene glycol, sodium lauryl sulfate, poloxamer (Pluronic), castor oil polyethylene glycol ether (Cremophor EL) or various PEG-derivatives (PEG-stearates, PEG-esters of fatty acids, PEG-derivatives of fatty acid glycerides, PEG-D-a-tocoferole) or complexing compounds such as cyclodextrins and their derivatives (hydroxypropyl-p-cyclodextrin), dextrans and their derivatives, pectins and their salts and derivatives, glucans and their derivatives, chitosan and its derivatives, methylcellulose and its salts and derivatives.
  • surfactants such as Tween 20, Tween 80, Macrogol 4000, Macrogol
  • Complexes/adducts can be prepared by mixing aqueous solutions of surfactants or complexing agents with alaptide. After completion of mixing a complex/adduct can be used for preparation of pharmaceutical compositions (formulations), or the solvent can be evaporated, and the obtained evaporation solid residue (a product of complexation) can be consequently used for the preparation of pharmaceutical compositions (formulations).
  • Alaptide nanoparticles can be obtained by milling alaptide with emulsifiers and other stabilizers. Alaptide nanoparticles were generated by dispergation using a technique of wet milling in the aqueous solution of a surface modifier. The suspension generated in this manner is milled using a ball mill in the presence of a milling medium. This method assumes pulverization of all major micrometer particles to nanoparticles. For example, deoxycholate sodium, sodium lauryl sulfate, poloxamer, povidone, Macrogol 6000 can be used as wetting agents. Grinding balls can be polystyrene, ceramic or glass.
  • Modified alaptide was obtained by the above-mentioned routes and showed considerably higher aqueous solubility and as well modified permeability through membranes. After evaporation of water from complexes/adducts it is possible to obtain solid surface-modified alaptide that can be used in pharmaceutical compositions (formulations) designed for human and/or veterinary applications as an individual medicinal substance (drug) or in the combination with other drugs such as non-steroidal anti-inflammatory drugs (otherwise nonsteroidal antiphlogistics or NSAIDs) and/or antipyretics/non-opiate analgesics and/or opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics (antibacterials/antimycobacterials, antimycotics, antivirotics) and/or antiparasitics and/or antihaemorhagics .
  • non-steroidal anti-inflammatory drugs otherwise nonsteroidal antiphlogistics or NSAIDs
  • semisolid formulations can be generally divided into oleo- hydro- ointments, oleo-/hydro-creams and gels.
  • Untreated, surface-modified and nanonized alaptide was added to ointment, cream and gel bases in the amount ranged from 0.1% to 5% of the total composition of formulation.
  • hydrofobic oleo-ointments the following excipients can be used:
  • mixtures of low- and high-molecular macrogols, 300 and 1500 (1:1), can be used as excipients.
  • Example of the composition of ointment with alaptide 1% w/w can be as follows: alaptide 1 g, cera lanae hydrosa 75 g, yellow vaseline 20 g, liquid paraffin up to 100 g.
  • Example of the composition of cream with alaptide 1% w/w can be as follows: alaptide 1 g, Cremor Neo-Aquasorbi ® 95 g, propylene glycol up to 100 g.
  • Example of the composition of gel with alaptide 1 % w/w can be as follows: alaptide 1 g, Carboxymethylcellulose ointment (carboxymethylcellulose sodium 5 g, Macrogol 300 10 g, propylene glycol 2.5 g, methylparaben 0.2 g, propylparaben 0.2 g, purified water 87.3 g) up to 100 g.
  • alaptide 1 g Carboxymethylcellulose ointment (carboxymethylcellulose sodium 5 g, Macrogol 300 10 g, propylene glycol 2.5 g, methylparaben 0.2 g, propylparaben 0.2 g, purified water 87.3 g) up to 100 g.
  • the particle size of the used micronized alaptide was measured by a microscope NIKON Optiphot 2 with a digital camera VDS CCD-1300F.
  • the particle size distribution of microcrystalline alaptide is 80% of particles up to 10 maximum Feret diameters.
  • the used nanonized alaptide was prepared using a nanomill NETZSCH with glass beads.
  • the particle size of the used nanonized alaptide was measured by NANOPHOX (0138 P) Sympatec equipment.
  • the medium size of the particles of nanonized alaptide is approx. 700 nm.
  • PAMPA Parallel Artificial Membrane Permeability Assays
  • Fig. 1 Influencing biotransformation enzymes CYP1A1, CYP1A2 and CYP1B1 in .. . . ⁇ . hepatocytes.
  • Fig. 2 Record of particle size determination of micronized alaptide.
  • Fig. 3 Record of particle size determination of nanonized alaptide.
  • Fig. 4 NIR spectra of the complex/adduct alaptide- Tween 20 (at the middle top) in comparison with the starting materials alaptide (entirely at the top) and Tween 20 (at s the middle bottom) and the subtracted spectrum of starting Tween 20 from the resulted spectrum of the obtained complex (entirely at the bottom).
  • Fig. 6 NIR spectra of the complex/adduct alaptide-Macrogol 6000 (at the middle top) in comparison with the starting materials alaptide (entirely at the top) and Macrogol 6000 (at the middle bottom) and the subtracted spectrum of starting Macrogol 6000 from the resulted spectrum of the obtained complex (entirely at the bottom).
  • Fig. 8 NIR spectra of the complex/adduct alaptide-Poloxamer (at the middle top) in comparison with the starting materials alaptide (entirely at the top) and Poloxamer (at the middle bottom) and the subtracted spectrum of starting Poloxamer from the resulted spectrum of the obtained complex (entirely at the bottom).
  • Fig. 9 NIR spectra of the complex/adduct alaptide-sodium carboxymethyl cellulose (at the middle top) in comparison with the starting materials alaptide (entirely at the top) and sodium carboxymethyl cellulose (at the middle bottom) and the subtracted spectrum of starting sodium carboxymethyl cellulose from the resulted spectrum of the obtained complex (entirely at the bottom).
  • Fig. 10 NIR spectra of the complex/adduct alaptide-sodium carboxymethyl dextran (at the middle top) in comparison with the starting materials alaptide (entirely at the top) and sodium carboxymethyl dextran (at the middle bottom) and the subtracted spectrum of starting sodium carboxymethyl dextran from the resulted spectrum of the obtained complex (entirely at the bottom).
  • Fig. 12 NIR spectra of the complex/adduct alaptide-pectan iec.-dibutylamide (at the middle top) in comparison with the starting materials alaptide (entirely at the top) and pectan sec.-dibutylamide (at the middle bottom) and the subtracted spectrum of starting pectan sec-dibutylamide from the resulted spectrum of the obtained complex (entirely at the bottom).
  • Fig. 13 In vitro evaluation of the penetration of micronized alaptide through the skin depending on time from various media.
  • Fig. 14 In vitro evaluation of the penetration of nanonized alaptide through the skin depending on time from various media.
  • Fig. 15 In vitro evaluation of the penetration of complexes/adducts of alaptide through the skin depending on time from phosphate buffer (pH 7.4).
  • Micronized alaptide was suspended in 10 mL of water (2 mg/mL) and mixed for 8 h at ambient temperature. Alaptide was not detected in the aqueous sample as a result of the performed analysis of the obtained sample (HPLC-DAD). To alaptide suspensions (2 mg/mL) the percentage by weight of surfactants or complexing agents was added, and their effect on alaptide dissolution was determined. The mixtures were mixed for 4 h at ambient temperature between the individual additions. After extinction of alaptide particles from mixtures, solvents were analyzed, and the detected concentration was approx. 2 mg/mL, ⁇ i.e. all added alaptide was dissolved), see Table 1. Then water was evaporated and it was found, according to NIR spectroscopy characterization that the dried product provided the required complex/adduct. Table 1: Concentration of individual excipients causing dissolution of alaptide in water.
  • the rotor speed was increased to 1500 rpm after 6 h of milling.
  • the total time of milling was 57.5 h.
  • the content of alaptide in the suspension was 38.76 g/L (determined by RP-HPLC).
  • PAMPA experiments on penetration of alaptide/modified alaptide were performed on commercially accessible BD GentestTM Pre-Coated PAMPA Plate System.
  • This is a lipophilic membrane, which surface is coated by phospholipids that simulate intestinal wall.
  • the amount of compound or nanosuspension corresponding to 10 mg of alaptide was weighed.
  • the donor samples were prepared by dissolving the tested samples in 40 mL of 0.01 M HC1, and after 15 min pH was adjusted using bicarbonate buffer to pH 6.
  • a carbonate buffer saline (physiological solution) with pH 7.4 was used as a receptor phase.
  • the receptor phase 200 uL/well was pipetted into the upper wells.
  • the donor phase was pipetted into the lower ones (300 ⁇ -, ⁇ ).
  • After the incubation time (5 h) 10 of the acceptor phase was taken from each well and mixed with physiological solution (990 uL). At least five determinations were performed.
  • the samples were determined by RP-HPLC method with UV-VIS detection. The results are summarized in Table 2.
  • Table 2 Achieved permeability of alaptide and its modifications using PAMPA plates.
  • oleo-ointment containing from 0.1 to 5% (w/w) of micronized alaptide or nanonized alaptide or a complex/adduct of alaptide with sodium lauryl sulfate or Poloxamer or Tween 20 or with other excipients from Table 1, where amount of alaptide corresponds the above mentioned percentage concentration, was prepared, and permeation experiments were performed according to Example 9.
  • hydro-ointment containing from 0.1 to 5% (w/w) of micronized alaptide or nanonized alaptide or a complex/adduct of alaptide with sodium lauryl sulfate or Poloxamer or Tween 20 or with other excipients from Table 1, where amount of alaptide corresponds the above mentioned percentage concentration, was prepared, and permeation experiments were performed according to Example 9.
  • oleo-cream containing from 0.1 to 5% (w/w) of micronized alaptide or nanonized alaptide or a complex/adduct of alaptide with sodium lauryl sulfate or Poloxamer or Tween 20 or with other excipients from Table 1, where amount of alaptide corresponds the above mentioned percentage concentration, was prepared, and permeation experiments were performed according to Example 9.
  • Example 9 100 g of gel containing from 0.1 to 5% (w/w) of micronized alaptide or nanonized alaptide or a complex/adduct of alaptide with sodium lauryl sulfate or Poloxamer or Tween 20 or with other excipients from Table 1, where amount of alaptide corresponds the above mentioned percentage concentration, was prepared, and permeation experiments were performed according to Example 9.
  • Example 9 100 g of gel containing from 0.1 to 5% (w/w) of micronized alaptide or nanonized alaptide or a complex/adduct of alaptide with sodium lauryl sulfate or Poloxamer or Tween 20 or with other excipients from Table 1, where amount of alaptide corresponds the above mentioned percentage concentration, was prepared, and permeation experiments were performed according to Example 9.
  • Example 9 100 g of gel containing from 0.1 to 5% (w/w) of micronized alaptide or nanonized alaptide or a complex/adduct
  • the receptor compartment (volume 5.2 mL) was filled with phosphate buffered saline (pH 7.4) and maintained at 37+0.5 °C using a circulating water bath.
  • the receptor compartment was continuously stirred using a magnetic stirring bar (800 rpm). Than a sample was applied to the skin surface, and the donor compartment of the cell was covered by Parafilm ® . Samples (0.5 mL) were taken from the receptor phase in time intervals, and the cell was refilled with an equivalent volume of the fresh buffer. For each compound, a minimum of three determinations were performed using skin fragments from a minimum of 2 animals.
  • Table 3 Permeability of micronized alaptide alone and in various semisolid formulations achieved in in vitro transdermal penetration experiments performed using Franz diffusion cell.
  • Table 4 Permeability of nanonized alaptide alone and in various semisolid formulations achieved in in vitro transdermal penetration experiments performed using Franz diffusion cell.
  • Table 5 Permeability of alaptide from complexes/adducts with excipients achieved in in vitro transdermal penetration experiments performed using Franz diffusion cell.

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Abstract

La présente invention concerne une manière de solubiliser l'alaptide par ajout de composés de masse moléculaire faible ou élevée ou par génération de nanoparticules. Ces modifications technologiques de l'alaptide influencent la pénétration de l'alaptide dans les membranes biologiques, y compris la peau. L'alaptide modifié de cette manière peut également être utilisé pour la préparation de compositions pharmaceutiques (formulations), qui peuvent, à leur tour, influencer l'absorption de l'alaptide.
PCT/CZ2012/000074 2012-08-02 2012-08-02 Alaptide : procédé de solubilisation, et de modification de la perméation membranaire, et compositions pharmaceutiques pour applications humaines et/ou vétérinaires WO2014019556A1 (fr)

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CN107903303A (zh) * 2017-11-20 2018-04-13 陕西慧康生物科技有限责任公司 一种环肽Alaptide的液相合成方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107903303A (zh) * 2017-11-20 2018-04-13 陕西慧康生物科技有限责任公司 一种环肽Alaptide的液相合成方法
CN107903303B (zh) * 2017-11-20 2021-06-04 陕西慧康生物科技有限责任公司 一种环肽Alaptide的液相合成方法

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