WO2013015674A1 - Nanostructures de collagène - Google Patents

Nanostructures de collagène Download PDF

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Publication number
WO2013015674A1
WO2013015674A1 PCT/MY2012/000210 MY2012000210W WO2013015674A1 WO 2013015674 A1 WO2013015674 A1 WO 2013015674A1 MY 2012000210 W MY2012000210 W MY 2012000210W WO 2013015674 A1 WO2013015674 A1 WO 2013015674A1
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WIPO (PCT)
Prior art keywords
collagen
nanostructure
nanostructures
formulation
diameter
Prior art date
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PCT/MY2012/000210
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English (en)
Inventor
Ghulam Nabi Qazi
Farhan Jalees AHMAD
Mohd SAMIM
Deborah COOPER
M. Rajendran V. MARNICKAVASAGAR
Original Assignee
Holista Biotech Sdn Bhd
Jamia Hamdard
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Application filed by Holista Biotech Sdn Bhd, Jamia Hamdard filed Critical Holista Biotech Sdn Bhd
Publication of WO2013015674A1 publication Critical patent/WO2013015674A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces

Definitions

  • the present invention relates to a collagen nanostructure, formulations comprising the same, methods for production of the same, as well as uses thereof.
  • the invention relates to collagen nanostructures such as nanoparticles, liposomes, micelles and/or niosomes.
  • Collagen is the principal component of connecting tissues of mammals. By itself, it is a relatively weak immunogen, at least partially due to masking of potential antigenic determinants within the collagen structure. It is also resistant to proteolysis due to its helical structure. Collagen is a natural substance for cell adhesion and the major tensile load-bearing component of the musculoskeletal system. Thus, extensive efforts have been devoted to the production of collagen fibres and membranes suitable for use in medical, as well as veterinary applications.
  • Collagen preparations for use in various medical applications are typically prepared from skin, tendons (e.g., bovine Achilles, tail, and extensor tendons), hide or other animal parts, by procedures involving acid and/or enzyme extraction.
  • Methods for collagen preparation usually involve purification of collagen by extraction with diluted organic acids, precipitation with salts, optional gelation and/or lyophilization, tangential filtration and the like.
  • An example of the method includes first separating fascia, fat and impurities from tissue. The tissue is then subjected to moderate digestion with proteolytic enzymes, such as pepsin. The collagen is then precipitated at a neutral pH, redissolved and the residual impurities precipitated at an acid pH.
  • the resultant tissue is then digested with a strong alkali and then exposed to acid to facilitate swelling.
  • the collagen fibres are then precipitated with salts or organic solvents, and dehydrated as disclosed in US patent no. 5,028,695.
  • the extracted collagen can further be converted into a finely divided fibrous collagen by treating water-wet collagen with acetone to remove water, centrifuging to obtain the solid mass of collagen and disaggregating the collagen during drying as provided in U.S. Pat. No. 4,148,664.
  • the collagen preparation can then be brought back to a neutral pH and dried in the form of fibres.
  • Completely transparent, physiological and hemocompatible gels, collagen films, and solutions can be prepared from the collagen resultant preparation. These forms of collagen may then be used in the fabrication of contact lenses and implants.
  • the penetration of collagen into skin is a major problem.
  • the penetration is linked to the degree of permeability of the skin (which is linked to its physiological condition) and to the physicochemical properties of the compounds which need to enter the skin.
  • molecular weight, polarity, ionization stage and the like of the compound together with the nature of the environment (excipient, carrier and the like used in the compound together) affect whether the compound is going to penetrate the skin.
  • the skin serves numerous functions, but its primary function is as a protective layer or barrier.
  • the most important role of the skin for terrestrial animals is to protect the water- rich internal organs from the dry environment.
  • This cutaneous barrier function of the skin resides in the upper most thin layer (approximately 10-20 pm in humans) called stratum corneum.
  • stratum corneum The water impermeability of this layer is 1000 times-higher than that of other membranes of living organisms.
  • the present invention provides a collagen nanostructure with a diameter less than 300nm.
  • the nanostructure may be a nanoparticle, liposome, micelle and/or noisome.
  • the nanostructure may be capable of enhanced penetration and/or retention effect in at least one cell relative to a control.
  • the present invention provides a collagen nanostructure formulation comprising a plurality of nanostructures according to any aspect of the present invention.
  • at least 70% of the nanostructures in the formulation have a diameter less than 250nm.
  • the present invention provides a method of producing a collagen nanostructure and/or a collagen nanostructure formulation according to any aspect of the present invention, the method comprising the steps of:
  • the present invention provides a collagen nanostructure and/or collagen nanostructure formulation prepared according to the method of the present invention, a method of treating a disease, in particular a skin disease by administering the collagen nanostructure and/or formulation according to any aspect of the present invention and/or the collagen nanostructure and/or formulation according to any aspect of the present invention for use in treating a disease, use of the collagen nanostructure and/or formulation according to any aspect of the present invention for the preparation of a medicament and uses thereof.
  • preferred embodiments of the present invention allow an optimal use of the collagen nanostructures to take advantage of their size, penetration and/or retention. This and other related advantages will be apparent to skilled persons from the description below.
  • Figure 1 is a size statistic report from Malvern Dynamic Light Scattering technology showing the dynamic light scattering pattern of collagen nanoparticles and that the formulation comprising the nanoparticles is monodispersed with an average diameter of 131nm with at least about 19% of the nanoparticles smaller than 100nm.
  • Figure 2 is a Transmission Electron Microscopy (TEM) Micrograph showing the morphology and size of collagen nanoparticles which is less than 100nm in diameter.
  • Figure 3A is a graph of the dynamic light scattering pattern of an example of a collagen formulation comprising collagen liposomes (LP-23) showing the size distribution by intensity with an average diameter of 114.9nm.
  • Figure 3B is graph showing the zeta potential of an example of a collagen formulation comprising collagen liposomes (LP-23).
  • Figure 3C is a size statistic report from Malvern Dynamic Light Scattering technology showing the dynamic light scattering pattern of collagen liposomes and that the formulation comprising the liposomes is monodispersed with an average diameter of 114.9nm.
  • Figure 4A is a graph of the dynamic light scattering pattern of an example of a collagen formulation comprising collagen niosomes (NS-63) showing the size distribution by intensity with an average diameter of 331.Onm.
  • Figure 4B is graph showing the zeta potential of an example of a collagen formulation comprising collagen niosomes (NS-63).
  • Figure 4C is a size statistic report from Malvern Dynamic Light Scattering technology showing the dynamic light scattering pattern of collagen niosomes and that the formulation comprising the niosomes is monodispersed with an average diameter of 331.0nm.
  • Figure 5 is an image of gel electrophoresis showing the collagen purity of collagen used in preparation of formulations comprising collagen nanostructures with a diameter less than 100nm
  • Figure 6 are images of confocal laser scanning microscopy of skin after application of formulations comprising collagen nanoparticles loaded with Rodamine showing penetration capacity of the collagen nanoparticles.
  • Figure 7 are enlarged images of confocal laser scanning microscopy of skin after application of formulations comprising collagen nanoparticles loaded with Rodamine showing penetration capacity of the collagen nanoparticles.
  • Figure 8 are images of Z sectioning of skin after application of formulations comprising collagen nanoparticles loaded with Rodamine showing penetration capacity of the collagen nanoparticles.
  • Figure 9A and B are gamma sciuntigraphic images of human volunteers after application of formulations comprising collagen liposomes on the back, pre-wash and post-wash respectively to show retention, uptake and penetration capacity of the collagen liposomes and niosomes.
  • Figure 9C and D are gamma sciuntigraphic images of human volunteers after application of formulations comprising collagen liposomes on the hands, pre-wash and post-wash respectively to show retention, uptake and penetration capacity of the collagen liposomes and niosomes.
  • Figure 10 shows the different means by which the collagen nanostructures according to any aspect of the present invention may permeate and enter the skin surface.
  • ⁇ is used herein to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of ⁇ 5%, ⁇ 10%, ⁇ 20%, ⁇ 25% or ⁇ 30% of the value specified. For example, “about 50nm” can in some embodiments carry a variation from 45nm to 55nm. In another embodiment, for example, a nanoparticle of about 100nm in diameter refers to a nanoparticle of 70-130nm in diameter.
  • ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof as well as the individual values making up the range, particularly integer values.
  • a recited range e.g., size of nanostructures
  • Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc.
  • each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.
  • cold temperature refers to a temperature below human body temperature.
  • cold temperature can be any temperature below 38°C.
  • the temperature may be 30°C, 25°C, 20°C, 15°C, 10°C, 8°C, 5°C and the like.
  • drug refers to any biologically active agent, including but not limited to classical small-molecule drugs, therapeutically effective proteins, lipids, polysaccharides, proteoglycans, and polynucleotides.
  • the drug may be a therapeutic, a prophylactic, or a diagnostic agent.
  • the term "enhanced penetration and/or retention” refers to improved permeation into the skin surface by the collagen nanostructure and retaining in the skin for longer period of time according to any aspect of the present invention and/or improved preservation of the nanostructure and its effects in a target region compared to other collagen nanostructures known in the art.
  • the collagen nanostructure according to any aspect of the present invention has been proven to penetrate the skin surface of humans and/or animals efficiently and effectively and/or is capable of maintaining its form and effect in the skin epithelium beneath the skin surface longer than the collagen nanostructures known in the art.
  • the enhanced penetration and/or retention of the collagen nanostructures can be measured using confocal microscopy and/or in vitro permeation study taught in Examples 9 and 10 below.
  • a collagen nanostructure may be said to have enhanced penetration and/or retention using in vitro permeation study if it has a maximum permeation of collagen of 1 % to 15%, 2% to 10%, 3% to 6% or the like and retention within the skin of 2% to 10%, 2% to 8%, 2% to 5% or the like.
  • Other examples known in the art may also be used to measure penetration, retention of the nanostructures and/or human gammascintigraphic study.
  • formulation refers to any nanostructure according to any aspect of the present invention intended for the administration of a . pharmaceutical compound, or combination, including, but not limited to, any chemical or peptide, natural or synthetic, that is administered to a patient for medicinal purposes.
  • a formulation may comprise either a single nanostructure or a plurality of nanostructures.
  • the term "liposome” refers to a particle comprising one or more lipid bilayers enclosing an interior, typically an aqueous interior.
  • a liposome is often a vesicle formed by a bilayer lipid membrane.
  • the liposomes according to any aspect of the present invention may by small, multilamellar or unilamellar.
  • the liposomes of the present invention are collagen liposome comprising at least one dimension having a size less than 300nm.
  • the diameter of the liposome may be less than or equal to 300nm, less than 250nm, less than 200nm, less than 150nm, less than 100nm or less than 50nm.
  • the term "micelle” refers to a collagen based aggregate of surfactant molecules dispersed in a liquid colloid.
  • the micelle according to the present invention when in aqueous solution forms an aggregate with the hydrophilic "head” regions in contact with surrounding solvent, sequestering the hydrophobic single tail regions in the micelle centre. This phase is caused by the insufficient packing issues of single tailed lipids in a bilayer.
  • a monodisperse refers to a collection of objects having the same size and shape.
  • a monodisperse of the nanoparticles according to any aspect of the present invention comprises nanoparticles of the same size and shape.
  • nanostructure refers to an extremely small particle.
  • nanostructure as used herein refers to an extremely small particle.
  • the nanostructure may comprise at least one dimension having size ⁇ 1000 nm. For example, ⁇ 700nm, 500nm, 300nm, 250nm, 200nm, 150nm or 100nm, in particular, ⁇ 50nm and even more in particular, less than 50 nm. More in particular, the nanostructure may comprise at least one dimension of size ⁇ 25 nm, and even more in particular the nanostructure may comprise at least one dimension of size ⁇ 10 nm or ⁇ 5 nm. The dimension may refer to the average diameter of the nanostructure.
  • nanostructure may be used to describe a nanoparticle, liposome, micelle or niosome etc.
  • the nanoparticle according to any aspect of the present invention may comprise at least one dimension having a size in the range of 1 to 200 nm. For example, 180nm, 150nm, 130nm or 100nm, in particular, 50nm and even more in particular, less than 50 nm.
  • the nanoparticle may comprise at least one dimension of size 25 nm, and even more in particular the nanoparticle may comprise at least one dimension of size 10 nm or 5 nm.
  • the dimension may refer to the average diameter of the nanoparticle.
  • the term "niosome” refers to a non-ionic surfactant-based liposome. Niosomes are formed mostly by cholesterol incorporation as an excipient. Other excipients can also be used.
  • the noisome according to any aspect of the present invention may comprise at least one dimension having a size less than 300nm. In particular, the diameter of the niosome may be less than or equal to 300nm, less than 250nm, less than 200nm, less than 150nm or less than 100nm.
  • water for injection refers to water that is purified by distillation or two-stage reverse osmosis.
  • zeta potential is a measure of the magnitude of the repulsion or attraction between particles. Its measurement brings detailed insight into the dispersion mechanism and is the key to electrostatic dispersion control thus can be used to determine stability.
  • Malvern Instruments' Zetasizer systems can be used to measure zeta potential measures.
  • the present invention is directed towards the production of nanostructures of collagen.
  • any solubilised collagen known in the prior art can be used.
  • These collagens can be extracted and purified from the connective tissue of various organs such as skin, bone, cartilage, tendon, and viscous of animals such as cows, pigs, birds, kangaroos, sheep and so forth by acidic solubilisation, alkaline solubilisation, neutral solubilisation and or enzymatic solubilisation, but also includes chemically-modified collagen and the like.
  • the collagen can be processed to produce collagen nanoparticles.
  • the collagen nanostructure may have at least one dimension that is less than or equal to 300nm.
  • the dimension may a diameter of a regularly shaped nanostructure (for example a sphere) or the largest dimension of an irregularly shaped nanostructure. More in particular, the dimension may be from 50nm to 200nm, from 50nm to 100nm, from 80nm to 250nm, from 80nm to 280nm, from 70nm to 290nm and the like.
  • the collagen nanostructure may be a nanoparticle, liposome, micelle, noisome and the like.
  • the nanostructure may be a nanoparticle with a diameter less than or equal to 100nm, 80nm, 50nm or the like.
  • the collagen nanostructure may be a liposome with a diameter less than 300nm, 200nm, 150nm, 100nm or the like.
  • the collagen nanostructure may be a niosome with a diameter less than less than 300nm, 200nm, 150nm, 100nm or the like.
  • the collagen nanostructures according to any aspect of the present invention may be capable of enhanced penetration and/or retention across at least one biological surface relative to a control.
  • the penetration and/or retention are a measure of the percentage of collagen nanostructures that pass across the biological surface and/or remain within a region beneath the biological surface.
  • the biological surface may be a skin surface of a human being and/or an animal and the region beneath the biological surface may be an epidermal region.
  • the control may be a collagen nanostructure not according to any aspect of the present invention. More in particular, the control may be a collagen nanostructure with a diameter greater than 300nm.
  • the enhanced penetration and/or retention may be due to:
  • Nano size lipophilic vesicle settle down to close contact with the skin and carrying collagen might penetrate into the skin (trans-cellular pathway)
  • follicular transport may also involve along with the other mechanism in collagen dermal deposition as shown in Figure 10.
  • the present invention provides a collagen nanostructure formulation comprising a plurality of collagen nanostructures according to any aspect of the present invention where at least 70% of the nanostructures have a diameter less than 250nm.
  • at least 70% of the nanostructures have a diameter less than 100nm, 80nm, 50nm or the like. More in particular, at least 75%, 80%, 85%, 90% or 95% of the nanostructures have a diameter less than 100nm, 80nm, 50nm or the like.
  • the nanostructures may be nanoparticles, wherein at least 70% of the nanoparticles may have a diameter less than 300nm, 200nm, 100nm, 80nm or 50nm.
  • the nanostructures may be liposomes, wherein at least 70% of the liposomes may have a diameter less than 300nm, 250nm, 200nm or 100nm.
  • the nanostructures may be niosomes, wherein at least 70% of the niosomes may have a diameter less than 300nm, 250nm, 200nm or l OOnm.
  • the present invention provides a method of producing a collagen nanostructure and/or collagen nanostructure formulation according to any aspect of the present invention comprising the steps of:
  • the present invention provides a collagen nanostructure and/or formulation prepared according to the method of any aspect of the present invention.
  • the process of the invention may involve preparing two independent solutions before mixing them, then adding a cross-linker solution to the mixture of solutions and then stirring the mixture, for example overnight, in order to achieve the collagen nanostructures of the present invention.
  • the first solution may comprise a plurality of collagen particles.
  • the plurality of collagen particles may be dissolved at cold temperature.
  • the second solution may comprise a plurality of metallic nanostructures which may be prepared by reducing metallic ions with a reducing agent and in particular, capped by a polymer to prevent further growth.
  • the process for producing a plurality of collagen nanostructures may comprise the steps of:
  • the collagen used in the present invention includes but is not limited to low molecular weight collagen and/or hydrolyzed collagen.
  • the collagen may be thoroughly dissolved by mixing in water for injection, particularly at the cold temperature in the range of 0-10°C. In particular, the collagen may be thoroughly dissolved by mixing at 5°C.
  • the collagen may then be mixed with metallic nanostructures.
  • the metallic nanostructures include but are not limited to silver nanoparticles, gold nanostructures, iron nanostructures, copper nanostructures, zinc nanostructures, nickel nanostructures, lead nanostructures and the like.
  • the metallic ions may be first reduced with a reducing agent before mixing with the collagen.
  • the reducing agent includes but is not limited to Sodium borohydride, Hydrazine Hydrate and Lithium Aluminium Hydride.
  • the metallic nanoparticles are capped by polymer to prevent further growth.
  • the polymer includes but not limited to polyacrylic acid, poly vinyl alcohol, poly (N-isopropylacrylamide), poly (ethylenimine) poly (N-vinyl-2-pyrrolidone) and the like.
  • the silver nanostructures may be prepared in an aqueous solution by reducing Ag + ions with Sodium Borohydride. The silver nanostructures may then be capped by polyacrylic acid to prevent further growth.
  • the collagen may be mixed with the metallic nanoparticle by vortexing.
  • a cross-linker may then be added to the mixture and stirred overnight.
  • the cross-linker may include but is not limited to Malondialdehyde, EDCI ⁇ 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride ⁇ , Glutaraldehyde pentasodium tripolyphosphate (TPP) and the like.
  • the resultant collagen nanostructures may be in the form of liquid dry powder and/or granule.
  • Dried collagen nanostructures can be obtained by a further step of drying.
  • the drying process may include but is not limited to freeze-drying, desiccation by evaporation at low temperature spray-drying and the like.
  • a combination of various analytical techniques can be used to elucidate the size and structure of collagen nanostructures of the present invention.
  • These techniques include UV-vis, Dynamic Light Scattering (DLS), Brunauer-Emmett-Teller (BET) specific surface area, Transmission Electron Microscopy (TEM), X-ray diffraction and the like.
  • TEM imaging may be used to verify the particle size and morphology characteristics, in conjunction with X-ray diffraction data for surfactant molecules thus being able to give greater insights to the supramolecular structure of the protective layer.
  • SDP precipitation technique may be unique in being able to control the size of the produced nanostructures and TEM results may support the DLS sizing data and may demonstrate low aspect ratio particle morphologies.
  • the process for producing collagen nanostructures comprises the steps of:
  • the process for producing collagen nanostructures according to any aspect of the present invention comprises the steps of:
  • the process for producing collagen nanostructures according to any aspect of the present invention comprises the steps of:
  • the process for producing collagen nanostructures according to any aspect of the present invention comprises the steps of:
  • the collagen nanostructures of the invention may be suitable for preparation of compositions for topical or parenteral use.
  • said nanostructures may be administered in doses corresponding to an amount of collagen ranging from 0.01 to 5 mg/kg of body weight, more preferably ranging from 2 to 3 mg/kg.
  • the concentration of collagen nanostructures may range from 1 to 25% weight/volume.
  • the nanostructures of the present invention may optionally contain an amount of viscosizing substance which may range from 0.1 to 0.4% by weight.
  • the present invention relates to the use of collagen nanostructures for incorporation and delivery of therapeutic agents or drugs.
  • Any drug that may be capable of being transformed into a microstructure or nanostructure material together with collagen may be formed into nanostructures using the method according to any aspect of the present invention.
  • the drug may be in either small molecule or macromolecular forms.
  • the drug may be of low solubility in bodily fluids or completely soluble in bodily fluids.
  • the extremely small particle size of the collagen nanostructures in the present invention can be useful in delivery of a suitable drug as an aerosol to the nasal passages and sinuses, or to the lungs and the like.
  • the method may be also useful in preparation of dosage forms of shear-sensitive drugs, such as proteins and nucleic acids.
  • shear-sensitive drugs such as proteins and nucleic acids.
  • the collagen nanostructures may be used alone, or may be coated with one or more surface-active agents ("surfactants"), polymers, adhesion promoters, or other additives or excipients.
  • surfactants surface-active agents
  • the nanaoparticles of the present invention may be incorporated into tablets or capsules or other dosage forms, or encapsulated.
  • Many different excipients may be commonly used in drug formulations. Classes of excipients include, but are not limited to, "tableting aids, disintegrants, glidants, antioxidants and other preservatives, enteric coatings, taste masking agents, and the like. References describing such materials are readily available to and well-known by the practitioners in the art of drug formulations.
  • the excipients may be added during any of the steps described below for including surfactants in the nanostructures.
  • the excipient may be added during the formation of the nanostructure; during the dispensing of the nanostructures to form a dosage form; or during the administration of the nanostructures.
  • the selection of the additives or excipients may be determined in part by the projected route of administration. Any of the conventional routes (e.g. inhalation, oral, rectal, vaginal, topical, parenteral and the like) may be suitable for, and may be enhanced by, the use of the nanostructure drug formulations. Suitable formulations include but are not limited to oral formulations, aerosols, topical formulations, parenteral formulations, and implantable compositions.
  • the nanostructure drug formulations may be particularly suitable for delivering hydrophobic and other poorly-soluble drugs, such as those in bioavailability classes II and IV, by oral or aerosol administration, thereby replacing a parenteral route of administration currently being used.
  • the collagen nanostructures may contain a surfactant to eliminate or reduce aggregation of the particles.
  • the surfactant may adhere to the surface of the nanoparticles.
  • a surfactant may facilitate the dispersion of the nanostructures in any or all of the initial non-solvent mixtures in which the particle may be formed, the medium in which the nanostructures may be taken up for administration, and the medium (e.g. gastrointestinal fluid) into which the particle may be later delivered.
  • any surfactant may be useful for use with the collagen nanostructures.
  • Suitable surfactants include small molecule surfactants, often called detergents, macromolecules (i.e. polymers) and the like.
  • the surfactant may also contain a mixture of surfactants.
  • the surfactant may be preferably one that is approved by the FDA for pharmaceutical uses.
  • the surfactant may be one that is approved by the FDA for use in foods or cosmetics.
  • the surfactant may be present in any suitable amount.
  • effective surfactants may be present as only a small weight fraction of the collagen nanostructures, such as from 0.1 % to 10% (wt of surfactant/weight of the collagen).
  • Suitable polymers that may be used in the present invention as a surfactant may include soluble and water-insoluble, and biodegradable and non-biodegradable polymers, including but not limited to hydrogels, thermoplastics, and homopolymers, copolymers and blends of natural and synthetic polymers.
  • Representative polymers include hydrophilic polymers, such as those containing carboxylic groups, including polyacrylic acid.
  • Bioerodible polymers may include polyanhydrides, poly(hydroxyl acids) and polyesters, as well as blends and copolymers thereof.
  • Representative bioerodible poly(hydroxyl acids) and copolymers thereof include but are not limited to poly(lactic acid), poly(glycolic acid), poly(hydroxybutyric acid), poly (hydroxyvaleric acid), poly (caprolactone) , poly (lactide-co-caprolacto- ne), poly(lactide-co-glycolide) and the like.
  • Polymers containing labile bonds, such as polyanhydrides and polyorthoesters, can also be used optionally in a modified form with reduced hydrolytic reactivity.
  • Positively charged hydrogels, such as chitosan, and thermoplastic polymers, such as polystyrene can also be used.
  • Representative natural polymers which also can be used in any aspect of the present invention include proteins, such as zein, modified zein, casein, gelatin, gluten, serum albumin, and polysaccharides such as dextrans, polyhyaluronic acid and alginic acid.
  • Representative synthetic polymers include polyphosphazenes, polyamides, polycarbonates, polyacrylamides, polysiloxanes, polyurethanes and copolymers thereof. Celluloses also can be used. As defined herein the term "celluloses" includes naturally occurring and synthetic celluloses, such as alkyl celluloses, cellulose ethers, cellulose esters, hydroxyalkyl celluloses and nitrocelluloses.
  • Exemplary celluloses include ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate and cellulose sulfate sodium salt.
  • Polymers of acrylic and methacrylic acids or asters and copolymers thereof may be used in any aspect of the present invention.
  • Representative polymers which can be used include but are not limited to poly (methyl methacrylate) , poly(ethyl methacrylate), poly (butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) and the like.
  • polymers which can be used include but are not limited to polyalkylenes such as polyethylene and polypropylene; polyarylalkylenes such as polystyrene; poly(alkylene glycols), such as poly(ethylene glycol); poly(alkylene oxides), such as poly(ethylene oxide); and poly(alkylene terephthalates), such as poly(ethylene terephthalate) and the like.
  • Polyvinyl polymers can also be used, which, as defined herein includes polyvinyl alcohols, polyvinyl ethers, polyvinyl esters and polyvinyl halides.
  • Exemplary polyvinyl polymers include poly (vinyl acetate), polyvinyl phenol and polyvinylpyrrolidone and the like.
  • Polymers which alter viscosity as a function of temperature, shear or other physical forces may also be used.
  • Poly(oxyalkylene) polymers and copolymers such as poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) or poly(ethylene oxide)-poly(butylene oxide) (PEO-PBO) copolymers, and copolymers and blends of these polymers with polymers such as poly(alpha-hydroxy acids), including but not limited to lactic, glycolic and hydroxybutyric acids, polycaprolactones, and polyvalerolactones, can be synthesized or commercially obtained.
  • polyoxyalkylene copolymers are described in U.S. Pat. Nos. 3,829,506; 3,535,307; 3,036,118; 2,979,578; 2,677,700; and 2,675,619.
  • polymers can be obtained from sources such as Sigma Chemical Co., St. Louis, Mo.; Polysciences, Warrenton, Pa.; Aldrich, Milwaukee, Wis.; Fluka, Ronkonkoma, N.Y.; and BioRad, Richmond, Calif., or can be synthesized from monomers obtained from these or other suppliers using standard techniques.
  • wetting agents include but are not limited to mannitol, dextrose, maltose, lactose, sucrose, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., TWEEN), polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcel!ulose, hydroxyethylcellulose, hydroxy propylcellulose, hydroxypropylmethyl
  • Preferred dispersants include hydrophilic polymers and wetting agents.
  • the amount of dispersant in the formulation may be less than about 80%, more preferably less than about 75%, by weight of the formulation
  • the polymer for use as a dispersant may be polyvinylpyrroidone.
  • One or more surfactants or other excipients can be added to the collagen and/or collagen-drug combination in a number of ways.
  • a surfactant may be applied at one or more of several steps in the process of producing and dispensing nanostructures of the present invention.
  • the surfactant may be present in the initial solution of collagen or other nanostructure-forming material.
  • the surfactant may be present in the solvent that is mixed with the collagen or collagen-drug combination to form the nanostructures.
  • the surfactant may be added to a drug solution before precipitation with the collagen.
  • this method is particularly useful for small- molecule surfactants.
  • Any medical or veterinary condition that can be treated with collagen or a drug carried by the collagen nanostructures of the present invention and may be treated using the nanostructure collagen.
  • the formulation may be administered to treat a disease such as cancer and the like or to administer an oral vaccine, or for any other medical or nutritional purpose requiring uptake through the mucosa of the drug or bioactive to be delivered.
  • Collagen nanostructures may be administered to a patient by a variety of routes.
  • routes include, without limitation, oral delivery to the tissues of the oral cavity, the gastrointestinal tract and by absorption to the rest of the body; delivery to the nasal mucosa and to the lungs (pulmonary); delivery to the, skin, or transdermal delivery; delivery to other mucosa and epithelia of the body, including the reproductive and urinary tracts (vaginal, rectal, urethra); parenteral delivery via the circulation; delivery from locally implanted depots or devices and the like.
  • routes include, without limitation, oral delivery to the tissues of the oral cavity, the gastrointestinal tract and by absorption to the rest of the body; delivery to the nasal mucosa and to the lungs (pulmonary); delivery to the, skin, or transdermal delivery; delivery to other mucosa and epithelia of the body, including the reproductive and urinary tracts (vaginal, rectal, urethra); parenteral delivery via the circulation; delivery from locally implanted depots or
  • Solution TV 50ml of water for injection was poured in a round bottom flask and 0.001 gms of low molecular weight collagen (Ovicoll from Holista colltech Ltd.) was added and completely dissolved by mixing at temperature 0-5° C. This solution was termed as Solution TV.
  • silver nanoparticles were prepared in aqueous solution by reducing Ag + ions with sodium borohydride.
  • the metallic silver produced is immediately capped by polyacrylic acid to prevent further growth.
  • the silver nanoparticles were prepared in aqueous phase by chemical reduction of silver salt solution using sodium borohydride in the presence of polyacrylic acid as a capping agent.
  • 800 ⁇ of silver nitrate solution (5% w/v) and 800 ⁇ of polyacrylic acid (50%w/v) were thoroughly mixed in 40 ml double distilled water at 4° C with constant stirring. After mixing the solutions, the mixture was further stirred for another hour. 100 ml of 0.01 M ice- cooled NaBH 4 solution was then added to the stirred mixture and the resultant solution became a light green colour. The resultant solution was further stirred for about two hours at 4° C.
  • the solution was dialyzed through 24 kD dialysis bag for 3-4 hours against distilled water and the solution changed from light green to yellow in colour.
  • the dialyzed solution containing silver particles were diluted to get silver nanoparticles solution of known concentration to carry out the further reactions.
  • Table 1 Data produced from DLS study of nanoparticles i.e. average particle size and polydispersity index of that population Diameter (nm) % Intensity Width (nm)
  • Figure 2 shows that the morphology and size of nanocollagen was less than 100nm in diameter and well distributed.
  • Solution ' ⁇ ' In a typical set of reaction, 50ml of water for injection was taken in a round bottom flask and O.OOIgms of low molecular weight collagen was added and thoroughly dissolved by mixing at temperature 0-5°C. This solution is termed as Solution ' ⁇ '.
  • silver nanoparticles were prepared in aqueous solution by reducing Ag+ ions with sodium borohydride.
  • the metallic silver produced is immediately capped by polyacrylic acid to prevent further growth.
  • the detailed synthetic procedure of silver nanoparticles is as follows: The particles were prepared in aqueous phase by chemical reduction of silver salt solution using sodium borohydride in the presence of polyarylic acid as capping agent. 800 ⁇ of silver nitrate solution (5% w/v) and 800 ⁇ of polyacrylic acid (50%w/v) were thoroughly mixed up in 40 ml double distilled water at 4°C with constant stirring. After mixing the solutions the mixture was further stirred for another hour. 100 ml of 0.01 M ice-cooled NaBH 4 solution was then added to the stirred mixture when it became light green in colour. The resultant solution was further stirred for two hours at 4°C.
  • the solution was dialyzed through 24 kD dialysis bag for 3-4 hours against distilled water when the solution was changed from light green to yellow.
  • the dialyzed solution containing silver particles were diluted to get silver nanoparticles solution of known concentration to carry out the further reactions.
  • Solution TV 50ml of water for injection was taken in a round bottom flask and 0.001 gms of low molecular weight collagen was added and thoroughly dissolved by mixing at temperature 0-5°C. This solution is termed as Solution TV.
  • silver nanoparticles were prepared in aqueous solution by reducing Ag+ ions with sodium borohydride.
  • the metallic silver produced is immediately capped by polyacrylic acid to prevent further growth.
  • the detailed synthetic procedure of silver nanoparticles is as follows: The particles were prepared in aqueous phase by chemical reduction of silver salt solution using sodium borohydride in the presence of polyarylic acid as capping agent. ⁇ of silver nitrate solution (5% w/v) and 800 ⁇ of polyacrylic acid (50%w/v) were thoroughly mixed up in 40 ml double distilled water at 4°C with constant stirring. After mixing the solutions the mixture was further stirred for another hour. 100 ml of 0.01 M ice-cooled NaBH4 solution was then added to the stirred mixture when it became light green in colour. The resultant solution was further stirred for two hours at 4°C.
  • the solution was dialyzed through 24 kD dialysis bag for 3-4 hours against distilled water when the solution was changed from light green to yellow.
  • the dialyzed solution containing silver particles were diluted to get silver nanoparticles solution of known concentration to carry out the further reactions.
  • Liposomal formulations were prepared using ethanol injection method as mentioned by Pons et al, 1993 with slight modification. Appropriate ratio of phospholipid and cholesterol was dissolved in absolute ethanol (total concentration of mixture was varied from 10mg/mL to 100mg/mL); 1 mL bolus and rapid injection of organic phase was then injected in the aqueous phase (collagen solution) through 30 gauge syringe followed by stirring for 1 h to remove the ethanol completely. Finally, all the formulations were sonicated for desired time [amplitude 35% and pulse 3sec: 5sec (on: off)] maintaining the temperature below 350C.Vesicle formation becomes evident on the appearance of the characteristic opalescence of colloidal dispersions. Two different examples (A) and (B) are provided below.
  • Niosomes were prepared by using ethanol injection method with slight modification (Shaikh et al, 2010).
  • Span60 or Span20, tween 20, 40, 60, 80, Cremophore EL.RH, Triton X 100, Labrasol, Lauroglycol 90, Labrafil M and combinations and Cholesterol (Sigma Aldrich, SD fine chemicals, Delhi,, Colorcon, India) in the different ratios were dissolved in ethanol (total concentration of mixture was varied from 10mg/ml_ to 150g/ml_) to form organic phase.
  • An aqueous phase concentration 0.5mg/mL to 70mg/mL of collagen
  • 20mL of phosphate buffer pH 7
  • the aqueous phase was kept on a magnetic stirrer at temperature of 35 ⁇ 0.5°C and 500rpm. 1 ml_ bolus and rapid injection of organic phase was then injected in the aqueous phase through 30gauge syringe followed by stirring for 1 h to remove the ethanol completely.
  • the developed niosomes were sonicated by probe sonicator [Vibra-CellTM VC 750; Sonics, USA] for 0.5min-30min at amplitude 35% and pulse 3sec: 5sec (on: off) maintaining the temperature below 35°C. Two different examples (A) and (B) are provided below.
  • Niosomes prepared were measured using DLS and found to be of the size 50nm-300nm as shown in Figure 4.
  • the niosomes and liposomes made according to the method of the present invention have better permeation of collagen and retention within the skin.
  • formulation of 300 nm shows higher retention in the skin and less permeation across the skin.
  • Collagen nano formulations liposomal as well niosomal formulations
  • the collagen was labeled using 99m Tc, which was then used for preparation of liposome and niosomes.
  • the formulations were then applied on the hands at specific spots as per protocol. Pre-washing and post-washing images of the spots were taken. Percentage Skin deposition of the collagen were calculated for both liposomes as well as niosome. Negligible amount of collagen were found in the blood sample, when
  • Liposomal and niosomal formulations respectively showed around 300% and 350% increased skin retention of collagen in comparison to direct application as shown in Figure 9.

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Abstract

La présente invention concerne une nanostructure de collagène de diamètre inférieur à 300 nm, une formulation comprenant celle-ci, des procédés pour la production de celle-ci, ainsi que ses utilisations.
PCT/MY2012/000210 2011-07-25 2012-07-23 Nanostructures de collagène WO2013015674A1 (fr)

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