Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
• • 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
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • 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
  • A61K9/1658—Proteins, e.g. albumin, gelatin
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5052—Proteins, e.g. albumin

Definitions

• the invention relates to a delivery system based on polymeric materials to be used in the formulation of food supplements, the process for the manufacture thereof and the use thereof in the nutraceutical field.
• Changing the release performance in a delayed release system consists in releasing an active ingredient with a pre-programmed delay or as a result of pH changes.
• the active ingredient is generally incorporated in a pharmaceutical form coated with natural, semi-synthetic or synthetic polymers.
• widely used polymers among the synthetic coating polymers are methacrylic acid derivatives, or in general polymers containing carboxyl groups, which at acidic pH (stomach) are undissociated and confer insolubility to the coating, while at a more alkaline pH (bowels) solubilize allowing the release of the active ingredient dose contained in the core.
• plant polysaccharides are rarely used in the pharmaceutical/nutraceutical field for such application, due to poor reproducibility of the properties (molecular weight, polydispersity index), which do not guarantee a satisfactory release performance.
• the most used are semi-synthetic pH-sensitive cellulose derivatives.
• Zein is a plant protein (approximately 35 kDa) belonging to the prolamine class, which is water insoluble due to the presence of a large number of hydrophobic amino acids. Thanks to its hydrophobic nature, zein has been proposed as a coating material and recently as a drug carrier in the form of films, fibres and particles of different sizes.
• Vann Leeuwev et al Food Chemistry, Vol. 155, July 2014, p. 161-166, describe a zein colloidal dispersion for ferric ion encapsulation and the use of this system as a functional fortified food.
• US patent 5,356,467 discloses stable aqueous dispersions of zein that can be used as coatings for the controlled release of pharmaceutical, veterinary, health or food products in an environment free of inorganic solvents, and methods for the preparation of the above mentioned dispersions.
• Cyclodextrins are cyclic oligosaccharides obtained by hydrolysis and enzymatic cyclization of starch and are made up of glucopyranose units linked by alpha- 1,4 bonds. Based on the number of units, they are classified into alpha-cyclodextrins, consisting of six monosaccharide units, beta-cyclodextrins with seven units, and gamma-cyclodextrins with eight.
• Cyclodextrins have the ability to form inclusion complexes (the so-called “host-guest complexes”) with non-polar substances, or portions thereof, by means of a molecular complexation mechanism.
• the guest molecules arrange themselves into the lipophilic cavity of the cyclodextrin, forming a complex characterised by a complexation constant, which is a function of the affinity of the CD for the guest. Thanks to this property of theirs, CDs are able to increase the apparent water solubility of an active principle, its dissolution rate, stability and bioavailability.
• Cyclodextrins are able to interact with hydrophobic amino acids, forming supramolecular complexes capable of modifying the structure of proteins in the solid state.
• Cyclodextrins have been proposed for improving the stability of proteins in solution and in the solid state and promoting water-solubilisation of active substances.
• patent CN 103756360 B describes a method for the preparation of a micro- powder of a water-insoluble yellow corn pigment, which constitutes the core of the micro- powder particles, which is coated with a coating consisting of maltose, ⁇ -cyclodextrin, modified starch, zein and an emulsifying agent.
• US patent 20040109920 Al describes a formulation of a carotenoid that is sparingly soluble in water, complexed with cyclodextrins, and coated with a natural or synthetic oil or polymer. However, there is no description of controlled release properties for the systems described in CN 103756360 B and US 20040109920 Al .
• the cyclodextrin and carotenoid complex is a dispersion, which is coated by a suitable coating agent. This limits the probability of forming nanometer-sized particles and limits the usefulness of the coating only for increasing the stability of the particles formed by the carotenoid/cyclodextrin inclusion complex.
• the present invention provides a liquid pharmaceutical composition
• a liquid pharmaceutical composition comprising a stable hydroalcoholic colloidal dispersion (also referred to as "pseudolatex”) comprising polymeric particles of zein and ⁇ - cyclodextrin in suspension in a hydroalcoholic continuous phase, the particles having a mean diameter less than 1 ⁇ , preferably comprised within the range of from 100 nm to less than 1 ⁇ , more preferably comprised within the range of from 500 nm to less than 1 ⁇ , the pharmaceutical composition including at least one active ingredient incorporated in the particles.
• a stable hydroalcoholic colloidal dispersion also referred to as "pseudolatex”
• the particles having a mean diameter less than 1 ⁇ , preferably comprised within the range of from 100 nm to less than 1 ⁇ , more preferably comprised within the range of from 500 nm to less than 1 ⁇
• the pharmaceutical composition including at least one active ingredient incorporated in the particles.
• the active ingredient incorporated in the particles is a hydrophiiic or lipophilic pharmaceutical or nutraceutieal active ingredient, preferably a nutraceutical active ingredient selected from, the group consisting of iron bisglycinate or other iron salts, coenzyme Q 10. lycopene. ⁇ -carotene, lutein, zeaxanthin, tocopherol, boswellic acids, colecalciferol, ergocalciferol, N-palmitoylethanolamide.
• retinol retinol, resveratroi, curcurain, cr- lipoic acid, gingerols, silymarin, qitercetin, melatonin, acetyl carnitine, caniiiine. ilavonoids. diosmin. hesperidin, rutin, citieohne, glutathione and combinations thereof.
• Table i lists the most interesting active ingredients and the related logP.
• liquid pharmaceutical composition of the present invention is advantageously suitable for use in the preparation of systems for the controlled release of active ingredients, in particular controlled-release solid gastro-resistant pharmaceutical forms, such as granulates, tablets or capsules, which form a further aspect of the invention.
• controlled-release solid gastro-resistant pharmaceutical forms consist of or comprise a micro-powder obtained by spray-drying the liquid pharmaceutical composition of the invention.
• the method of preparing the liquid pharmaceutical composition of the invention is described hereinafter and forms a further aspect of the present invention, as well as the method of preparing the solid gastro-resistant pharmaceutical form starting from the liquid composition.
• the method of preparing the liquid pharmaceutical composition of the invention comprises the steps of:
• the liquid composition of the invention is used for preparing solid gastro-resistant pharmaceutical forms consisting of a micro-powder or comprising a micro- powder.
• the micro-powder is obtained by spray-drying the liquid pharmaceutical composition prepared as described above.
• the method of preparing the liquid pharmaceutical composition of the invention has some important advantages with respect to the prior art.
• the method described in CN 103756360 B requires homogenizing the dispersion of the carotenoid and the two coating phases, with considerable expenditure of energy.
• the active ingredient is in an aqueous solution or in the hydroalcoholic solution and is trapped in the polymer matrix by mixing the two solutions, with consequent precipitation of zein. In this way, there is no requirement for high amounts of energy and it is possible to obtain submicron-sized particles, which are not necessarily obtainable with the method of CN 103756360 B.
• the submicron particles obtained with the method of the present invention besides being stable in the continuous phase without generating agglomeration, allow, once dried into the micro-powder, a higher bioavailability of the carried active ingredient, its protection from the acidic environment of the stomach and a sustained release, which can be useful for active principles characterised by a short half-life.
• the mixing of the hydroalcoholic solution with the aqueous solution is carried out at room temperature, under continuous and moderate stirring for less than 5 hours.
• the weight ratio of ⁇ -cyclodextrin in the aqueous solution is comprised within the range of from 0.1 to 5% w/v, preferably from 0.1 to 2% w/v, more preferably approximately 1%.
• the concentration of zein in the hydroalcoholic solution is comprised within the range of from 1% to 10% w/v, preferably from 2% to 6% w/v, still more preferably approximately 4% w/v.
• the water-soluble active agents are directly added to the aqueous ⁇ - cyclodextrin solution.
• the liposoluble active agents can be added in advance to the hydroalcoholic zein solution or may be dissolved in the organic solvent used for zein and added to the zein/ -cyclodextrin colloidal dispersion.
• the term "active ingredient” is intended to mean both pharmacologically active compounds and compounds that have beneficial/health properties on the body, such as nutraceutical compounds.
• pharmaceutical composition and “solid pharmaceutical form” refer to compositions or solid dosage forms including pharmaceutical active ingredients or compounds having beneficial/health properties on the body, such as nutraceutical compounds.
• the formation of submicron-sized particles in suspension occurs as a result of the mixing of the hydroalcoholic zein solution with the aqueous ⁇ - cyclodextrin solution.
• the pseudolatex particles exhibit a mean diameter less than 1 ⁇ m, preferably comprised within the range of from 100 nm to less than 1 ⁇ m, even more preferably from 500 nm to less than 1 ⁇ .
• Zein and ⁇ -cyclodextrin form a complex during the formation of the pseudolatex and approximately 60% of ⁇ -cyclodextrin interacts with zein. The remaining 40% of ⁇ - cyclodextrin remains solubilized in the continuous phase of the pseudolatex.
• the pseudolatex is subjected to spray- drying, selecting as the operating parameter an inlet temperature preferably of about 1 15°C.
• the production yield of the powder is very high and equal to 90% of the theoretical quantity of solid components used in the preparation of the pseudolatex. It can be noted that the production yield is duplicated with respect to that obtainable by using zein as such (i.e. without ⁇ -cyclodextrin), demonstrating that the presence of ⁇ -cyclodextrin in the formation of the pseudolatex improves the process of production of the micro-powder by spray-drying.
• micro-powder obtained by spray-drying has been characterised and showed a mean diameter of between 2 and 8 microns, generally of approximately 5 ⁇ , and a tapped density ranging from 0.12 to 0.35 g/cm 3 , generally of approximately 0.255 g/cm 3 .
• a SEM analysis of the zein/ ⁇ -cyclodextrin microparticles was also performed, showing a partially spherical and collapsed morphology typical of powders prepared by spray-drying.
• the release of iron bisglycinate was performed in media simulating the biological environment (gastric fluid, intestinal fluid with enzymes) and prepared as indicated in the 12th edition of the Official Pharmacopoeia (also set forth in the 8th edition of the European Pharmacopoeia).
• Table 3 shows an intestinal medium at pH 6.8 with pancreatin, instead, a progressive increase in the percentage of released iron is observed, demonstrating an efficient control of the release rate (Table 3).
• the zein/ ⁇ CD combination allows the processing and incorporation of iron bisglycinate, which can not be included in the formulation in the absence of ⁇ CD.
• ⁇ -cyclodextrin In addition to being essential for obtaining powders containing different active ingredients, ⁇ -cyclodextrin also plays a central role in the preparation of thin films, which can be placed as a gastro-resistant coating on solid pharmaceutical forms including various types of active ingredients, so as to obtain solid gastro-resistant pharmaceutical forms including a core and a gastro-resistant coating.
• another aspect of the present invention is a controlled-release solid gastro- resistant pharmaceutical form consisting of a core, such as for example a granulate or a tablet, containing an active ingredient, the core being coated with a thin film obtained by drying a hydroalcoholic solution of zein and ⁇ -cyclodextrin optionally containing at least one plasticizer.
• a method for obtaining these solid gastro-resistant pharmaceutical forms comprises the steps of:
• a plastic support e.g. polyethylene, polyethylene terephthalate
• a density between 30 and 150 g/m 3 , more preferably 60 g/m 3
• temperatures comprised between 25 and 80°C, preferably at room temperature, to obtain a thin film
• the plasticizer is preferably selected from polyethylene glycol, polyols, fatty acids; more preferably, it is polyethylene glycol 400 (0.5-12% w/v).
• the hydroalcoholic solution of zein, ⁇ - cyclodextrin and at least one plasticizer is nebulized onto the core containing the active ingredient (for example a granulate or a tablet) in a heated gas flow at temperatures preferably between 25 and 80°C, to form a coating.
• the active ingredient for example a granulate or a tablet
• the method according to the present invention allows the achievement of thin films having a thickness of 0.1-2 mm, which are endowed with high flexibility.
• ⁇ -cyclodextrin in films obtained with the method described above, its amount in the film was modulated while keeping the zein/plasticizer (PEG 400) ratio fixed.
• the thickness of the films was directly dependent on the amount of ⁇ -cyclodextrin ⁇ CD) therein.
• ⁇ -cyclodextrin acts as a plasticizer and the modulation of the amount of cyclodextrin is fundamental to ensure the formation of coatings which meet the expected requirements.
• a further property given to films by ⁇ -cyclodextrin is that of ensuring gastroresistance compared to control films consisting of zein alone. This property was assessed by treating zein/ ⁇ CD films and control films consisting of zein alone with media simulating the biological environment as described previously and evaluating the flexibility of the films.
• films containing zein/ ⁇ CD showed no change in their morphological characteristics and flexibility, unlike what happens to control films consisting of zein alone, which stiffen and tend to break. This substantial difference indicates that ⁇ -cyclodextrin plays a fundamental role in bringing about the formation of gastro-resistant coatings, which remain unchanged while passing through the gastric tract.
• films containing zein/ ⁇ CD and respective zein-only control films are treated with simulated intestinal fluid, in the absence/presence of pancreatin, they lose their morphological and plastic characteristics, indicating that the coating is gastro-resistant only in the presence of ⁇ -cyclodextrin and degrades as the pH increases.
• solid gastro-resistant pharmaceutical forms including zein and ⁇ -cyclodextrin films/coatings according to the present invention, as well as the micro-powder described above, also show a remarkable gastroresistance attributable to the use of the combination of zein and ⁇ -cyclodextrin.
• Powder containing zein ⁇ CD iron bisglvcinate 50 mL of a hydroalcoholic solution (ethyl alcohol/water in a ratio of 8:2 v/v) containing 2 g of zein (4% w/v zein) were prepared.
• the hydroalcoholic zein solution was diluted with the aqueous ⁇ CD/iron bisglycinate solution (volume ratio 1 :1) causing the formation of submicron-sized particles in suspension.
• the mixing is carried out at room temperature, under continuous and moderate stirring for less than 5 hours.
• the obtained pseudolatex was dried by spray drying to obtain a micro-powder containing iron bisglycinate.
• Zein ⁇ CD curcumin powder 50 mL of a hydroalcoholic solution (ethyl alcohol/water in a ratio of 8:2 v/v) containing 2 g of zein (4% w/v zein) and 50 mg of curcumin were prepared.
• a hydroalcoholic solution ethyl alcohol/water in a ratio of 8:2 v/v
• zein 4% w/v zein
• aqueous solution containing 500 mg of ⁇ CD 50 mL of an aqueous solution containing 500 mg of ⁇ CD were prepared.
• the hydroalcoholic zein/curcumin solution was diluted with the aqueous ⁇ CD solution (volume ratio 1 :1) causing the formation of submicron-sized particles in suspension.
• the mixing is carried out at room temperature, under continuous and moderate stirring for less than 5 hours.
• Zein/ ⁇ CD film 1 mL of a hydroalcoholic solution (ethyl alcohol/water in a ratio of 8:2 v/v) containing 100 mg of zein and 4.2 mg of ⁇ CD was prepared, with 60 mg of polyethylene glycol 400 added.
• a hydroalcoholic solution ethyl alcohol/water in a ratio of 8:2 v/v
• the mixture containing zein, ⁇ CD and the plasticiser was poured on 7-cm diameter Teflon capsules. The drying was carried out at room temperature. 0.1 -mm thick films are obtained.

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Cited By (5)

Citations (6)

• 2017
  • 2017-05-05 IT IT102017000048797A patent/IT201700048797A1/it unknown
• 2018
  • 2018-05-04 WO PCT/IB2018/053113 patent/WO2018203294A1/en active Application Filing

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