Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
  • A61K31/728—Hyaluronic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
  • A61K36/535—Perilla (beefsteak plant)
• • 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
  • A61K47/02—Inorganic compounds
• • 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
  • A61K47/30—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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents

Definitions

• the present invention relates to a composition comprising an extract of vegetable origin, the use of such composition in the ophthalmic field, a single-use package comprising such composition.
• Perilla is an annual herbaceous plant belonging to the Laminaceae family, typical of southeast Asia and generally used for human consumption and as as a medicinal plant in traditional medicine, especially Chinese, Korean and Japanese traditional medicine (and is known as "Shiso").
• the leaves of Perilla Frutescens L. are known for their detoxifying, antitussive, antibiotic and antipyretic properties, moreover they are used in traditional medicine for the treatment of intestinal disorders and allergies (reference: Journal of Agricultural and Food Chemistry, 2005, 53, 8141-8147 -"DETERMINATION OF PHENOLIC COMPOUNDS IN PERILLA FRUTESCENS L. BY CAPILLARY ELECTROPHORESIS WITH ELECTROCHEMICAL DETECTION').
• the Perilla L. genus in turn includes four different species of Perilla, of which the most commonly cultivated is Perilla frutescens L. Britton, the other species being Perilla hirtella Nakai; Perilla seyatoensis G. Honda; Perilla citriodora Nakai.
• Other species of Perilla such as Perilla aguta Benth., Perilla albiflora Odash., Perilla ocimoides L. are ascribed to the Perilla frutescens species (reference: Acta Bote Pharmaceutica - Drug Research, Vol. 66 No. 4 pp.
• the leaves, but also the seeds, of this plant are particularly rich in polyphenolic substances including rosmarinic acid, luteolin and other derivatives thereof, caffeic acid, apigenin and other derivatives thereof, ferulic acid (reference: Journal of Agricultural and Food Chemistry, 2005, 53, 8141-8147 -'DETERMINATION OF PHENOLIC COMPOUNDS IN PERILLA FRUTESCENS L. BY CAPILLARY ELECTROPHORESIS WITH ELECTROCHEMICAL DETECTION”).
• the leaves there are several carotenoids including chlorophyll a, chlorophyll b, beta- carotene and lutein (reference: Food and Chemical Toxicology, 48, 2010, 264-270 - "DETERMINATION OF TOXIC PERILLA KETONE, SECONDARY PLANT METABOLITES AND ANTIOXIDATIVE CAPACITY IN FIVE PERILLA FRUTESCENS L. VARIETIES”).
• the red- green colored leaves of the frutescens variety of Per ilia Frutescens L.
• the seeds of the plants of the Perilla genus are instead rich in lipids, the overwhelming majority of which are triacylglycerols while a small proportion is made up of phytosterols.
• the fatty acids that make up the triacylglycerols are represented mostly by alpha-linolenic and linoleic acid, i.e. polyunsaturated fatty acids belonging to the omega-3 and omega-6 family, by oleic acid, monounsaturated, and other saturated fatty acids such as palmitic and stearic acid (Reference: Songklanakarin J. Ski. Technol. , 2006, 28 (Suppl. l): ⁇ l-2 ⁇ - " VARIATION OF LIPID AND FATTY ACID COMPOSITIONS IN THAI Perilla SEEDS GROWN AT DIFFERENT LOCATIONS".
• compositions are known for the topical administration of a substance or of combinations of substances used for the treatment or attenuation of a disorder in humans, by exerting a pharmacological, metabolic or immunological action (in which case they are referred to as medicines), or by way of a mechanical action, i.e. not a pharmacological or metabolic or immunological action (in which case they are referred to as medical devices).
• Such compositions can be in the form of solutions, both as an aqueous solution with low or medium viscosity, and as a gel with medium to high viscosity.
• the present invention relates to a composition with high biocompatibility which is suitable for ophthalmic administration comprising an extract of Perilla.
• composition of the invention enables the administration of active ingredients of natural origin in a formulation that is stable and can be standardized with regard to the polyphenol content.
• the extract is produced starting from leaves and seeds of at least one plant of the Perilla frutescens L. genus and in particular from Perilla ocymoides L. originating from China and Japan (Reference: EPO Data Sheet of Perilla 2.5% dry hydroalcoholic extract, rev. 2 of 10-09-2009).
• the Perilla extract is in the form of a dry hydroalcoholic extract comprising 2.5%, by weight of the total weight of the extract, of polyphenols derived from Perilla and wherein the Perilla extract is present in a percentage of from 0.1 % to 5% by weight of the total weight of the composition.
• the extract characterized by an Extract/Drug (E/D) ratio of 1 : 10, is obtained by way of extraction of the seeds and leaves of the plant in a 70:30 ethanol/water mixture.
• the extract is stabilized with maltodextrin from maize which are present in a maximum percentage of 30%.
• the extract does not contain preservative or antioxidant substances.
• the titer of total polyphenols is determined by way of Folin- Ciocalteu spectrophotometric analysis (Reference: EPO DATA SHEET FOR PERILLA 2.5% DRY HYDROALCOHOLIC EXTRACT, rev. 2 of 10-09- 2009).
• the presence of polyphenols of Perilla frutescens L. is the source of the antioxidant and antiallergic properties of the plant and of its extracts.
• the antioxidant action appears to work both by way of a contrasting action against free radicals (such as for example superoxide radicals), chelation of metals and acting as a reducing agent (primary antioxidant mechanism), and also by way of a metabolic interaction with induction or inhibition of specific cellular enzymes (secondary antioxidant mechanism) (Reference: Plant Food for Human Nutrition 2009, 10.1007/sl l 130-009-0152-x - "EFFECT OF SPINACIA OLERACEAE L. AND PERILLA FRUTESCENS L.
• the antiallergic property which renders the composition of the invention useful for contrasting, for example, allergic rhinoconjunctivitis, is also correlated with the composition of the extract of Perilla and specifically with the presence of rosmarinic acid, as well as other macromolecular compounds.
• the extract of Perilla in fact seems to be capable of influencing all three characteristic stages of type I allergic reactions, i.e.
• IgE antigen-specific immunoglobulin E
• the composition of the invention moreover comprises hyaluronic acid, in the form of sodium salt, polysaccharide polymer with high biocompatibility.
• hyaluronic acid in the form of sodium salt, polysaccharide polymer with high biocompatibility.
• This is in fact present in all body tissues and fluids in vertebrates, and in particular in the connective tissue.
• One of the parts of the body where the concentration of hyaluronic acid is highest is the vitreous body of the eye.
• Hyaluronic acid has a great capacity for hydration by retaining water molecules and in the hydrated state it exhibits a viscoelastic behavior that makes it an excellent lubricant (Reference: "Jo urnal of Internal Medicine 1997, 242, 27-33 "HYALURAN: ITS NATURE, DISTRIBUTION, FUNCTIONS AND TURNOVER”).
• Hyaluronic acid also has the property of making formulations more viscous, for the purpose of extending the time the formulation remains on the ocular surface (Reference: Clinical and Experimental Ophthalmology 1990, 225:510-512 - "PRECORNEAL RESIDENCE TIME IN HUMANS OF SODIUM HYALURONATE AS MEASURED BY GAMMA SCINTIGRAPHY').
• hyaluronic acid has also been known to be capable of modulating the healing of wounds without the formation of filamentous connective tissue and scars. The effect seems to be correlated to the presence of a high quantity of this macromolecule in the extracellular matrix at the site of the wound (Reference: Ann Surg. 1991 April; 213(4): 292-296 - STUDIES IN FETAL WOUND HEALING.
• the hyaluronic acid content is at least equal to 0.1% w/w and more preferably greater than 0.2% by weight of the total weight of the composition.
• the composition of the invention can be prepared in a form without preservatives, a characteristic that makes it possible to eliminate or in any case reduce to the minimum the possibility of allergic reaction and of interactions between the components of the composition.
• the preparation of a formulation without preservatives, both in terms of chemical properties and of microbiological properties (sterility), is made possible by the particular combination and choice of raw materials and of the manufacturing process.
• the chemical stability of the special composition of the invention which contains Perilla depends on the chemical stability characteristics of the components and in particular on the chemical stabilization of the hydroalcoholic extract of Perilla by way of maltodextrins.
• the microbiological stability depends on the type of production process applied (a process under aseptic conditions) together with the use of a sterile single-dose primary container, impermeable to microorganisms, in which the sterile product is dosed.
• the composition of the invention is in the form of eye drops, more preferably in the form of an aqueous solution or a gel.
• Another aspect of the invention relates to the composition comprising an extract of Perilla for use in the treatment of diseases and/or disorders in the ophthalmic field.
• a first type of composition of the invention [indicated hereinafter as Fl], which is represented by a solution with low viscosity (approximately 5 mPa*s - 15 mPa*s [Rheomat viscometer mod. L9 - 22°C]), is in turn subdivided into two formulation variants.
• the actions performed in the eye by the first formulation variant [indicated hereinafter as Fla] are; antioxidant, refreshing, diluent.
• the diluent action which is performed by way of the dilution and subsequent removal from the ocular surface of the excess liquid by blinking, enables the dilution and removal of allergens, dust and mucoid thickening agents from the ocular surface, thus being useful for the prevention and treatment of disorders caused by such factors and for the treatment and/or prevention of allergic rhinoconjunctivitis.
• the actions performed in the eye by the second formulation variant [indicated hereinafter as Fib] are: antioxidant, refreshing, diluent and hydrating.
• the hydrating action is attributed to the presence of a percentage of hyaluronic acid that is at least twice as much as that of the first variant.
• a second type of composition of the invention [indicated hereinafter as F2] is represented by a solution with medium viscosity, approximately 20 mPa « s - 100 mPa*s [Rheomat viscometer mod. L9 - 22°C].
• the actions performed in the eye are: antioxidant, hydrating, lenitive and wetting and are useful in particular for the attenuation of symptoms of dry eye due to unfavorable environmental conditions, of a moderate dry eye pathological state, of the prolonged use of contact lenses.
• a third type of composition of the invention [indicated hereinafter as F3] is represented by a gel with medium to high viscosity, approximately 600 mPa-s - 800 mPa*s [Rheomat viscometer mod. L9 - 22°C].
• the actions performed in the eye are: antioxidant, lubricant, lenitive and supplementing of the lipidic component of the lacrimal film and they are useful in particular for the treatment of pathological dry eye.
• the present invention relates to a single-use primary container, i.e. a phial made of plastic material that contains the formulations with extract of Perilla that are the subject matter of the present invention.
• the single-use primary container made of plastic is produced under controlled contamination conditions and subsequently, as a second step, is made sterile, usually by irradiation (gamma ray or beta ray sterilization) or alternatively with ethylene oxide (EO).
• irradiation gamma ray or beta ray sterilization
• EO ethylene oxide
• the composition according to the invention is formulated with a preparation process with controlled bacterial load that includes the steps of sampling and dispensing and mixing of the components; the subsequent partitioning step occurs under aseptic conditions.
• the composition that contains Perilla is sterilized by way of a filtration process (0.22 ⁇ ); alternatively - preferably for the compositions with medium to high viscosity (600 mPa-s - 800 mPa-s) such as the gel - the production process involves both the steps of preparation and partitioning occurring under aseptic conditions; this is due to the impossibility of sterilizing the viscous composition by filtration.
• benzalkonium chloride which is one of the preservatives most commonly used in the formulation of eyedrops, has been shown to have toxic effects in the laboratory, in experimental and clinical studies.
• a quaternary ammonium salt is capable of causing instability of the lacrimal film, loss of caliciform cells, conjunctival squamous metaplasia, apoptosis, deterioration of the corneal epithelium barrier and damage to the deeper ocular tissues (Reference: Prog Retin Eye Res, 2010 - PRESERVATIVES IN EYEDROPS: THE GOOD, THE BAD AND THE UGLY);
• formulations containing Perilla without preservatives can also be indicated for contact lens wearers; in fact the preservatives present in conventional formulations on sale usually tend to accumulate on contact lenses with the consequent risk of induction of toxic reactions such as in the case of chlorhexidine (a cationic substance), for which several studies have confirmed the tendency of the eye to develop an allergy when placed in contact over long periods with chlorhexidine, which tends to bond easily to the lipid/protein deposits present on soft contact lenses (Reference: GUF [Guida all'Uso dei Farmaci - translated title: Guide to Use of Pharmaceuticals] - from the Italian- language website www.guidausofarmaci.it, in the "oculistica” [ophthalmology] clinical section);
• a quaternary ammonium salt is capable of causing instability of the lacrimal film, loss of caliciform cells, conjunctival squamous metaplasia, apoptosis, deterioration of the corneal epithelium barrier and damage to the deeper ocular tissues (Reference: Prog Retin Eye Res, 2010 - PRESERVATIVES IN EYEDROPS: THE GOOD, THE BAD AND THE UGLY);
• the preservative in fact is a chemical component, within the formulations commonly on sale, the purpose of which, generally, is solely to keep the proliferation of bacteria under control and, differently from other excipients, it does not contribute to increasing either the effectiveness or the tolerability of the substances contained in the formulation and, on the contrary, it has the disadvantage of being capable of provoking adverse effects in the user.
• Example 1 Formula Fla non-viscous
• the solution ranges from odorless to slightly odorous, with a odor pleasant odor
• Viscosity 7 mPa-s (acceptance range: 5 mPa-s - 9 mPa-s) [measured with Rheomat viscometer mod. L9 - at a temperature of 22°C, Rl rotor, speed 8 rpm]
• Example 2 Formula Fib non- viscous
• Example 3 Formula F2 having medium viscosity
• Viscosity 25 mPa-s (acceptance range: 20 mPa-s - 100 mPa-s)
• the F3 formulation was studied in terms of the quality and quantity of the excipients so as to obtain a formulation that is relatively liquid under non-physiological conditions, i.e. at the pH and temperature of formulation (respectively 4.5 and ambient temperature), but which in a physiological environment, i.e. when applied on the ocular surface, undergoes a phase modification thus forming a gel that is more viscous than the initial formulation, making it possible to extend the period of time the formulation remains on the ocular surface.
• Carbopol 980 is a polyacrylic acid polymer that undergoes a transition from the liquid state to a gel when the formulation that contains it comes into contact with aqueous solutions that are capable of increasing its pH above its pK of approximately 5.5.
• This effect can also be obtained by inserting a combination of Carbopol and other viscosifiers, such as for example hydroxypropyl methyl cellulose (HPMC), in the formulation (Reference: The Pharmaceutical Society of Japan, 2007 - PREPARATION AND EVALUATION OF A CARBOPOL®/HPMC-BASED IN SITU GELLING OPHTHALMIC SYSTEM FOR PUERARIN and Lubrizol TDS-730 VISCOSITY OF CARBOPOL® POLYMERS IN AQUEOUS SYSTEMS).
• HPMC hydroxypropyl methyl cellulose
• the Carbopol 980 NF gel moreover exhibits a non-Newtonian behavior, substantially pseudo-plastic (specifically Ellis plastic, reference: Lubrizol PHARMACEUTICAL BULLETIN 7 FLOW AND SUSPENSION PROPERTIES).
• the administration of ophthalmic preparations should interfere as little as possible with the pseudo-plastic characteristics of the precorneal film.
• viscoelastic formulations such as the formulations with Carbopol, which are characterized by a viscosity that is high in conditions of low shear rate and low in conditions of high shear rate (Reference: Pak. J. Pharm. Ski., 2009 SUSTAINED OPHTHALMIC DELIVERY OF OFLOXACIN FROM AN ION-ACTIVATED IN SITU GELLING SYSTEM).
• Carbopol is a substance with mucoadhesive properties (Reference: The Pharmaceutical Society of Japan, 2007 - PREPARATION AND EVALUATION OF A CARBOPOL®/HPMC- BASED IN SITU GELLING OPHTHALMIC SYSTEM FOR PUERARIN
• in-vitro tests of the F3 composition have been conducted to verify and quantify the sol/gel change of state under physiological conditions, i.e. after instillation of the formulation in the eye, i.e. pH 7.4 and a temperature of 37°C.
• the Fl .a, Fl .b, F2 and F3 formulations described in the examples given above were subjected to a preliminary chemical/physical stability study at room temperature and at 4°C.
• the experimental data measured confirmed the stability of the organoleptic characteristics (appearance and odor) and of the chemical-physical characteristics (pH, osmolality and viscosity) of such formulations after 5 months of storage under environmental test conditions.
• Mathematical extrapolation of the stability data to a longer storage period suggests that the critical parameters defined in the specifications are kept over time.

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Citations (5)

• 2010
  • 2010-12-30 IT IT000369A patent/ITMO20100369A1/it unknown
• 2011
  • 2011-12-28 WO PCT/IB2011/055992 patent/WO2012090170A1/en active Application Filing

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